Reasons for lack of referral to medical oncology for systemic therapy in stage IV non-small-cell lung cancer: comparison of 2003-2006 with 2010-2011.

INTRODUCTION: Only approximately 25% of stage iv non-small-cell lung cancer (nsclc) patients receive systemic therapy. For such patients, we examined factors affecting referral to a cancer centre (cc) and to medical oncology (mo), and use of systemic therapy. METHODS: Using the Glans-Look Lung Cancer database, we completed a chart review of stage iv nsclc patients diagnosed in Southern Alberta during 2003-2006 and 2010-2011, comparing median overall survival (mos), referral, and treatment in the two cohorts. RESULTS: Of the 922 patients diagnosed in 2003-2006 and the 560 diagnosed in 2010-2011, 94% and 82% respectively were referred to a cc, with 22% and 23% receiving traditional chemotherapy (tctx). Referral to a cc or mo and use of tctx correlated with survival (p < 0.0001): The mos duration was 11.2 months in those receiving tctx and 1.0 months in those not referred to a cc. The overall mos duration was similar in the two cohorts (4.1 months vs. 3.9 months, p = 0.47). Major reasons for lack of referral to mo included poor functional status, rapid decline, and patient wish, which were similar to the reasons for forgoing tctx. In the two cohorts, 87 (9.4%) and 42 (7.5%) patients received epidermal growth factor inhibitors, with a mos duration of 16.2 months. Multivariable analysis showed that male sex [hazard ratio (hr): 1.16; p = 0.008] and pulmonary embolus (hr: 1.2; p = 0.002) correlated with worse survival. In contrast, receipt of chemotherapy (hr: 0.5; p < 0.001) and enrolment in a clinical trial (hr: 0.76; p = 0.049) correlated with better survival. CONCLUSIONS: Our experience confirms that, over time, uptake of systemic therapy, including tctx and targeted therapy, changed little despite their established efficacy. Most of the factors limiting systemic therapy uptake appear to be non-modifiable at the time of referral. Rapid diagnosis and the availability of well-tolerated drugs for all nsclc patients will likely be the most important factors in increasing systemic therapy uptake in this population.

Bortezomib-induced hyponatremia: tolvaptan therapy permits continuation of lenalidomide, bortezomib and dexamethasone therapy in relapsed myeloma.

The development of hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) is well recognised in multiple myeloma (MM). SIADH, due to either MM or Bortezomib can be hazardous as severe hyponatremia may develop if large volumes of hypotonic intravenous fluid are used as an adjunct to chemotherapy. We report a case of Bortezomib-induced SIADH, in whom the use of tolvaptan, a vasopressin receptor-2 antagonist, permitted the continuation of triple combination anti-MM therapy with lenalidomide, Bortezomib and dexamethasone (RVD) in a female with aggressive disease, without the development of hyponatremia. Our patient had a rapid relapse, in which the use of Bortezomib as part of an RVD regimen was life-saving. The use of tolvaptan allowed continuation of therapy that is usually halted in other similarly reported cases. This case highlights the possible use of vaptans, which allows an aquaresis to occur by blocking the antidiuretic effects of vasopressin, as a treatment for Bortezomib-induced hyponatremia.

Afatinib in advanced pretreated non-small-cell lung cancer- a Canadian experience.

Background: Afatinib, an irreversible epidermal growth factor receptor tyrosine kinase inhibitor (egfr tki), is approved for first-line therapy in advanced EGFR mutation-positive non-small-cell lung cancer (nsclc) and has previously demonstrated activity after failure of chemotherapy and reversible egfr tkis, with improved response and progression-free survival, compared with placebo. Outcomes in pretreated patients with advanced nsclc receiving afatinib through a Canadian special access program (sap) are reported here. Methods: Patients with nsclc progressing after at least 1 line of chemotherapy and an egfr tki were eligible to enrol in the sap. Characteristics of patients from the two largest accruing Canadian centres were retrospectively reviewed, including demographics, disease and treatment data, and patient outcomes. Results: The 53 patients who received afatinib (57% women, 51% never-smokers, 26% of East Asian ethnicity, and 66% with adenocarcinoma) had a median age of 59 years. EGFR mutations were documented in 25%, and EGFR wild-type in 8%. All patients had received prior egfr tki treatment, with 42% achieving a response. Patients took afatinib for a median of 2 months (range: 0-26 months); 17% required 1 or more dose reductions. Of 47 evaluable patients receiving afatinib, 10 experienced tumour shrinkage, and 11, stable disease. Median survival from afatinib initiation was 5 months (95% confidence interval: 2 months to 8 months). Grade 3 or greater diarrhea, rash, paronychia, and stomatitis were seen in 9%, 11%, 6%, and 4% of patients respectively. Conclusions: In an unselected population of pretreated patients with advanced nsclc after tki failure, median survival with afatinib therapy was 5 months. Through a sap, afatinib demonstrated activity in clinical practice, with manageable toxicity.

The prognostic role of microsatellite instability in colorectal cancer patients.

BACKGROUND: Data from the literature regarding the prognostic role of DNA mismatch repair system (MMR) in colorectal cancer are still controversial. AIM: The aim of the study was to identify the prognostic role of different phenotypic, clinical and pathological characteristics in microsatellite unstable vs. microsatellite stable colorectal cancer in terms of survival and disease free interval. METHODS: We conducted a retrospective study that included a total of 103 patients who underwent curative surgery for colorectal cancer. Immunohistochemistry testing revealed MLH1, MLH2, MLH6, PMS2 genes and mutations of the BRAF gene. We identified three groups of patients: patients with colorectal tumors with MSI produced by hypermethylation, (MLH1/BRAF+) group, patients with microsatellite instable tumours produced by genetic mutations MSI groupb(MLH1, MLH2, MLH6, PMS2) and patients with microsatellite stable tumours (MSS). RESULTS: The study shows that: MSI tumours (MLH1/BRAF+) group occur more frequently in women (p=0.05), on the right side of the colon (p=0.001). The 5-year survival rate was higher in patients with MSI tumours (MLH1/BRAF+) group than in those with microsatellite stable tumours, the differences were not statistically significant ; relapse rate was higher in patients with MSI tumors than in those with MSI tumours (MLH1/BRAF+) group (p=0.03) or with MSS tumors (p=0.004). CONCLUSIONS: The identification of microsatellite unstable colorectal tumours is an important molecular marker with role in recognition subgroups of patients with different phenotypic characteristics, survival and relapse rates. KEY WORDS: Colorectal cancer, Mismatch repair genes, Prognostic role.

Correction of moderate and severe acquired flexible flatfoot with medializing calcaneal osteotomy and flexor digitorum longus transfer.

BACKGROUND: Acquired flexible flatfoot encompasses a wide spectrum of disease, and there is no validated treatment protocol. We hypothesized that a medializing calcaneal osteotomy with a flexor digitorum longus transfer is adequate to correct a less severe acquired flexible flatfoot but not a more severe flatfoot. We also hypothesized that use of an additional procedure would further correct the flatfoot. METHODS: The study included seven pairs of cadaver specimens, with one side randomly selected for the creation of a mild flatfoot deformity and the other, for the creation of a severe flatfoot deformity. Cyclic axial load was applied to the intact foot, to the flatfoot, after correction with a medializing calcaneal osteotomy and a flexor digitorum longus transfer, and after the addition of a subtalar arthroereisis. Radiographic and pedobarographic data were obtained at each stage. A repeated-measures analysis of variance with post hoc analysis was used to compare all parameters in the intact foot with those in the flatfoot and corrected specimens. A Student t test was used to compare flatfoot severity between the mild and severe models. RESULTS: Compared with the intact foot, the mild and severe flatfoot models showed a significant change in the talar-first metatarsal angle (p = 0.01 and 0.03, respectively), talonavicular angle (p = 0.04 and 0.04), and medial cuneiform height (p = 0.03 and 0.05). The mild and severe models were significantly different from each other with regard to the talar-first metatarsal angle (p = 0.003) and talonavicular angle (p = 0.002). After the osteotomy and tendon transfer in the mild-flatfoot model, the talar-first metatarsal angle and talonavicular angle were not significantly different from those in the intact state. In the severe-flatfoot model, the talar-first metatarsal angle, talonavicular angle, and medial cuneiform height remained significantly undercorrected after the osteotomy and tendon transfer. After the arthroereisis, the talonavicular angle and medial cuneiform height were not significantly different from the values for the intact foot. CONCLUSIONS: In a cadaver model, the effectiveness of different procedures on radiographic and pedobarographic parameters varies with the severity of an acquired flatfoot deformity.

Fusarium sp. growth inhibition by wheat germ agglutinin.

The antifungal role of wheat germ agglutinin (WGA) isolated from a Romanian dihaploid variety of wheat against two pathogenic fungal species of Fusarium, F. graminearum and F. oxysporum, is demonstrated. WGA was prepared from unprocessed wheat germs by a new purification procedure using chitin and fetuin-Sepharose as affinity chromatography supports. SDS-PAGE and chitinase assay showed that the WGA preparation migrated as a single protein band and was devoid of any contaminating enzyme chitinase, well known for its antifungal effects. Based on its affinity for N-acetylglucosamine residues, WGA binding to the chitin-containing walls of the fungi was detected by fluorescence microscopy using WGA coupled with fluorescein isothiocyanate (FITC). In vitro testing of WGA action on early developmental stages of both fungal strains resulted in various modifications of the germ tubes, visualised by light microscopy: swelling, vacuolation of the cellular content and lysis of cell walls. Viability tests performed on potato tuber slices showed that the microbial infection was prevented from spreading by pretreatment of the fungal suspension with WGA.

Zinc in health and chronic disease.

Zinc is a trace element essential for the optimal function of a variety of biochemical and physiological processes. Its role in healthy aging is particularly important as it prevents neo plastic cell growth, is involved in mitotic cell division, DNA and RNA repair. Although zinc is widely available in food, the daily intake in many persons may be suboptimal. Other causes of low zinc concentrations may be due to small bowel conditions that cause mucosal damage and thus decrease absorption. Chronic diseases associated with alterations in zinc status are bronchial asthma, rheumatoid arthritis and Alzheimer disease. At present it is uncertain if therapy with zinc would assist in the management of these chronic diseases. In view of the important cellular functions of zinc in the human body, a diet with an adequate zinc content is beneficial in promoting healthy aging and maintaining good health.

Plantar pressures in the forefoot after lateral column lengthening: a cadaver study comparing the Evans osteotomy and calcaneocuboid fusion.

BACKGROUND: Excessive varus alignment of the forefoot after lateral column lengthening has been reported to lead to overloading of the lateral foot. The purpose of this study was to investigate whether there is a difference between the Evans opening wedge calcaneal osteotomy (Evans) and the calcaneocuboid distraction arthrodesis (CCDA) with respect to lateral forefoot loading. METHODS: In each of 12 matched pairs of cadaver feet, plantar pressure measurements of the intact specimens were obtained during simulated foot-flat and early heel-rise phases of gait and again after randomly performing the Evans procedure on one foot and the CCDA on the other foot. Cervical plate fixation was used for immediate stability. RESULTS: Both procedures resulted in statistically significant increased loading of the lateral forefoot and decreased loading of the medial forefoot compared with the preoperative status. The relative increase in lateral pressures was statistically greater with the CCDA than with the Evans. The average increase in pressure under the fifth metatarsal head in the foot-flat phase was 46% +/- 42% (range-4% to 141%) with the Evans and 104% +/- 58% (range 9% to 216%) with the CCDA (p = 0.003). In the early heel-rise phase, the increase in pressure was 50% +/- 43% (range 2% to 108%) and 96% +/- 65% (range 12% to 263%), respectively (p = 0.02). CONCLUSION: The experimental data suggest that lateral column overload may be more likely with the CCDA than with the Evans. Physicians should be aware of the likelihood of increasing lateral column loads with both the CCDA and the Evans procedure. It may be possible to avoid this problem by using less lateral column lengthening than the 1 cm used in this study or by considering a medial column arthrodesis or plantarflexion osteotomy to balance forefoot loading.

Oculoleptomeningeal Amyloidosis associated with transthyretin Leu12Pro in an African patient.

Oculoleptomeningeal amyloidosis is a rare manifestation of hereditary transthyretin (TTR) amyloidosis. Here, we present the first case of leptomeningeal amyloidosis associated with the TTR variant Leu12Pro mutation in an African patient. A 43-year-old right-handed Nigerian man was referred to our centre with rapidly progressive neurological decline. He presented initially with weight loss, confusion, fatigue, and urinary and erectile dysfunction. He then suffered recurrent episodes of slurred speech with right-sided weakness. He went on to develop hearing difficulties and painless paraesthesia. Neurological examination revealed horizontal gaze-evoked nystagmus, brisk jaw jerk, increased tone, brisk reflexes throughout and bilateral heel-shin ataxia. Magnetic resonance imaging showed extensive leptomeningeal enhancement. Cerebrospinal fluid analysis showed a raised protein of 6.4 g/dl. Nerve conduction studies showed an axonal neuropathy. Echocardiography was characteristic of cardiac amyloid. TTR gene sequencing showed that he was heterozygous for the leucine 12 proline mutation. Meningeal and brain biopsy confirmed widespread amyloid angiopathy. TTR amyloidosis is a rare cause of leptomeningeal enhancement, but should be considered if there is evidence of peripheral or autonomic neuropathy with cardiac or ocular involvement. The relationship between different TTR mutations and clinical phenotype, disease course, and response to treatment remains unclear.

A comparison of the penetration of two quinolones into intra-abdominal abscess.

A low-mortality model of an intra-abdominal abscess in the rat has been used to study the penetration of two quinolone agents into pus. Maximum concentrations in pus after intravenous injections were achieved at four hours (ciprofloxacin: 12.7 +/- 3.69 mg/L, fleroxacin: 2.25 +/- 1.82 mg/L), whereas fleroxacin given orally reached the maximum level at two hours (13.39 +/- 3.13 mg/L). Higher concentrations of fleroxacin were recorded in pus than in serum at each time point up to eight hours after administration, but pus levels of ciprofloxacin only exceeded serum levels after 1.5 hours. These antibiotics appear to have a unique property of high penetration into established abscesses and may have an important therapeutic role in the treatment of patients with multiple interloop abscesses.

New advances in antibiotic prophylaxis for colorectal surgery.

The major advances in antibiotic prophylaxis in colorectal surgery have come from an awareness of the need for appropriate agents against the known likely pathogens and from knowledge of the pharmacokinetics of these drugs. Intensive study has been undertaken to identify optimal regimens, but as there is great variability in the settings under which these operations take place, it is not always possible to compare the results of these various investigations. There is little doubt that in many cases there is gross contamination with faecal organisms and the term prophylaxis is inappropriate so that prolonged courses of antibiotics would appear to be safer. However, work towards identifying patients at increased susceptibility of developing septic complications may well further improve the outcome of colorectal surgery.

A post-marketing surveillance survey on the use of dipotassium clorazepate in clinical practice in the Philippines.

A post-marketing surveillance survey of dipotassium clorazepate usage was carried out in the Philippines between July 1990 and April 1991. Data were analyzed on 562 patients suffering from conditions in which anxiety was a major component. The results suggest that the medication was prescribed in accordance with the generally accepted best practice for benzodiazepines. Overall, 85% of patients were reported to have recovered and only 2% reported minor side-effects. Dipotassium clorazepate was thus confirmed to be a highly effective and relatively safe anxiolytic agent.

Dynamic updating in DIAS-NIDDM and DIAS causal probabilistic networks.

Diabetes advisory system (DIAS) is a decision support system, which has been developed to provide advice on the amount of insulin injected by subjects with insulin-dependent diabetes mellitus (IDDM). DIAS employs a temporal causal probabilistic network (CPN) to implement a stochastic model of carbohydrate metabolism. The CPN network has recently been extended to provide also advice to subjects with noninsulin-dependent diabetes mellitus (NIDDM). However, due to increased complexity and size of the extended CPN the calculations became unfeasible. The CPN network was, therefore, simplified and a novel approach employed to generate conditional probability tables. The principles of dynamic CPN's were adopted and, in combination with the method of conditioning, learning, and forecasting, were implemented in a time- and memory-efficient way. An evaluation using experimental data was carried out to compare the original and revised DIAS implementations employing data collected by patients with IDDM, and to assess the a posteriori identifiability of model parameters in patients with NIDDM.

Pott's puffy tumor, frontal sinusitis, frontal bone osteomyelitis, and epidural abscess secondary to a wrestling injury.

A blow sustained to the head while wrestling may produce frontal osteomyelitis and its complications, Pott's puffy tumor and epidural abscess. The symptoms may be minimal and may be manifested only by a mild headache and occasional stuffy nose. A 16-year-old boy was studied one month after a head injury sustained while wrestling, complaining only of recurrent headaches and fever. A fluctuant mass was found in the midfrontal area. Frontal sinusitis, subperiosteal abscesss epidural abscess, and frontal osteomyelitis were found at surgery. The frontal bone involved by the osteomyelitis was debrided, and the epidural abscess was evacuated.

Comparative subacute effects of dietary raw soya flour on the pancreas of three species, the marmoset, mouse and rat.

Subacute changes induced in the pancreas by raw soya flour have been studied in three species. The raw soya flour was fed to male Sprague-Dawley rats and male CD-1 mice for 2, 4 or 8 days at a level of 50% (w/w) in the diet, and to male and female marmosets for 2 or 7 days at 20% (w/w) in the diet. The stathmokinetic method was used to study mitotic activity in the pancreas, and mean acinar cell area was calculated using an image analysis system. The relative weight of the pancreas in the rat and mouse increased during dosing, but that of the marmoset did not. No proliferative or trophic effects were observed in marmoset pancreas, but in both the mouse and rat a transient increase in mitotic activity was followed by a steady increase in acinar cell size.

Three procedures for increasing vocal response to therapist prompt in infants and children with Down syndrome.

The relative effectiveness of three procedures for increasing vocal response to prompt in 15 preschool children with Down syndrome was compared. The procedures were positive reinforcement only, positive reinforcement combined with light-dimming, and positive reinforcement combined with visual screening. All procedures produced a significant increase in percentage of response to prompt over baseline, however, light-dimming and screening, when combined with positive reinforcement, were both significantly more effective than positive reinforcement alone. Implications for increasing early vocal interaction in children with Down syndrome and other developmental delays were discussed.

Drug disposition and dosage determination of once daily administration of gentamicin sulfate in horses after abdominal surgery.

OBJECTIVE: To evaluate pharmacokinetics of once daily i.v. administration of gentamicin sulfate to adult horses that had abdominal surgery. DESIGN: Prospective study. ANIMALS: 28 adult horses that underwent abdominal surgery for colic. PROCEDURE: 14 horses were treated with each dosage of gentamicin (i.e., 6.6 or 4 mg/kg, i.v., q 24 h) and blood samples were collected for pharmacokinetic analysis. Plasma gentamicin concentrations were measured by use of a fluorescence polarization immunoassay. Pharmacokinetic analysis measured the elimination half-life, volume of distribution, and gentamicin total systemic clearance. Treatment outcome, CBC, and serum creatinine concentrations were recorded. RESULTS: 1 horse in the high-dosage group died. All other horses successfully recovered, and did not develop bacterial infection or have evidence of drug toxicosis resulting in renal injury. Mean pharmacokinetic variables for gentamicin administration at a high or low dosage (i.e., 6.6 or 4 mg/kg, i.v., q 24 h) were half-life of 1.47 and 1.61 hours, volume of distribution of 0.17 and 0.17 L/kg, and systemic clearance of 1.27 and 1.2 ml/kg/min, respectively. Mean serum creatinine concentration was 1.74 and 1.71 for the high and low dosages, respectively, and serum creatinine concentration was not correlated with gentamicin clearance. CONCLUSIONS AND CLINICAL RELEVANCE: Gentamicin administration at a dosage of 4 mg/kg, i.v., every 24 hours, will result in plasma concentrations that are adequate against susceptible bacteria with a minimum inhibitory concentration (MIC) of < or = 2.0 micrograms/ml. Gentamicin administration at a calculated dosage of 6.8 mg/kg, i.v., every 24 hours will result in optimum plasma concentrations against susceptible bacteria with a MIC of < or = 4.0 micrograms/ml.

Endoscopic treatment of suspected infectious intertubercular bursitis in a horse.

A 9-year-old gelding was evaluated because of a 30-day history of mild intermittent left forelimb lameness. The only detectable abnormality was mild atrophy of the musculature of the proximal portion of the left forelimb. The cause of the lameness could not be determined. The horse was discharged from the hospital, but was reexamined 6 weeks later because of worsening of the lameness. At that time, the horse resisted flexion and extension of the left shoulder joint, and results of evaluation of an ultrasound-guided aspirate of fluid from the intertubercular bursa were suggestive of infection. Endoscopic examination of the bicipital bursa revealed synovial hypertrophy, particularly in the distal aspect of the bursa. The bursa was lavaged, and a synovial resector was used to remove inflamed synovium. The horse recovered and was healthy 4 months later. In this horse, endoscopy allowed adequate examination of the intertubercular bursa and was not technically difficult.

DIAS-NIDDM--a model-based decision support system for insulin dose adjustment in insulin-treated subjects with NIDDM.

A decision support system has been developed, Diabetes Insulin Advisory System for patients with non-insulin dependent diabetes mellitus (DIAS-NIDDM), assisting in the adjustment of insulin doses in insulin-treated subjects. DIAS-NIDDM uses a causal probabilistic network (CPN) model of carbohydrate metabolism to make stochastic predictions of blood glucose (BG) excursions. The CPN model is an extension of an existing model with an added component representing endogenous insulin secretion. A linear relationship between BG and insulin concentration due to BG stimulated insulin secretion is assumed. Model parameters (pancreatic sensitivity, insulin sensitivity, and time-to-peak of NPH insulin) are estimated by Bayesian probability updating from patient's specific data (food intake, insulin doses, BG measurements) recorded over a period of 4 days. The estimated parameters allow the system to be potentially used as a diagnostic tool to identify abnormalities of carbohydrate metabolism: impaired insulin secretion, insulin resistance and the severity of the impairments. DIAS-NIDDM was used to predict patient-specific BG profiles and advise on insulin doses during a pilot study in eight patients with NIDDM of whom five were treated with insulin. Compared to the administered insulin amount, daily insulin amount advised by DIAS-NIDDM was similar (within 4 U) in three patients, higher by 20% (19 U) in one patient and lower by 40% (18 U) and 50% (11 U) in two patients, respectively. The inter-day coefficient of variation of the daily insulin advice suggests that, at least according to DIAS-NIDDM criteria, day-to-day adjustment of insulin doses is necessary to maintain optimum control.

Pediatrics: ridding children of common worm infections.

The most common worm infection in children in the United States is pinworm infection. In second place is roundworm infection. Agents that are effective against these nematodes in a high proportion of cases are available. In hookworm disease, generally seen in older children, tetrachloroethylene treatment is being supplanted by use of drugs less likely to have adverse side effect. Visceral larva migrans is difficult to diagnose and to treat, and our best hope for control lies in prevention.