Epidermal growth factor receptor inhibitor-induced hypomagnesemia: a survey of practice patterns among Canadian gastrointestinal medical oncologists.

Background: The optimal management of hypomagnesemia (hMg) induced by epidermal growth factor receptor inhibitors (egfris) for advanced colorectal cancer is unclear. We surveyed gastrointestinal medical oncologists in Canada to determine practice patterns for the management of egfri-induced hMg. Methods: Based on distribution lists from the Eastern Canadian Colorectal Cancer Consensus Conference and the Western Canadian Gastrointestinal Cancer Consensus Conference, medical oncologists were invited to participate in an online questionnaire between November 2013 and February 2014. Results: From the 104 eligible physicians, 40 responses were obtained (38.5%). Panitumumab was more commonly prescribed than cetuximab by 70% of respondents, with 25% prescribing cetuximab and panitumumab equally. Most respondents obtain a serum magnesium level before initiating a patient on an egfri (92.5%) and before every treatment (90%). Most use a reactive strategy for magnesium supplementation (90%) and, when using supplementation, favour intravenous (iv) alone (40%) or iv and oral (45%) dosing. Magnesium sulfate was used for iv replacement, and the most common oral strategies were magnesium oxide (36.4%) and magnesium rougier (18.2%). Under the reactive strategy, intervention occurred at hMg grade 1 (70.3%) or grade 2 (27%). Of the survey respondents, 45% felt that 1-5 of their patients have ever developed symptoms attributable to hMg, and 35% have had to interrupt egfri therapy because of this toxicity, most commonly at grade 3 (30%) or grade 4 (45%) hMg. The most important question about egfri-induced hMg was its relevance to clinical outcomes (45%) and its symptoms (37.5%). Conclusions: In Canada, various strategies are used in the management of egfri-induced hMg, including prophylactic and reactive approaches that incorporate iv, oral, or a combination of iv and oral supplementation. Clinicians are concerned about the effect of hMg on clinical outcomes and about the symptoms that patients experience as a result of this toxicity.

Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17.

BACKGROUND: Right- and left-sided colon cancers (RC, LC) differ with respect to biology, pathology and epidemiology. Previous data suggest a mortality difference between RC and LC. We examined if primary tumour side also predicts for outcome in chemotherapy refractory, metastatic colon cancer (MCC). We also compared RC versus LC as a predictor of efficacy of epidermal growth factor receptor (EGFR) inhibition with cetuximab. METHODS: Reanalyzing NCIC CO.17 trial (cetuximab versus best supportive care [BSC]), we coded the primary tumour side as RC (caecum to transverse colon) or LC (splenic flexure to rectosigmoid). The association between tumour side and baseline characteristics was assessed. Cox regression models determined factors affecting overall survival (OS) and progression free survival (PFS). RESULTS: Patients with RC (150/399) had more poorly differentiated, mutant KRAS, mutated PIK3CA and wild-type BRAF tumours, fewer liver and lung metastases, and shorter interval between diagnosis and study entry. Among BSC patients, tumour side was not prognostic for PFS (hazard ratios (HR) 1.07 [0.79-1.44], p = 0.67) or OS (HR 0.96 [0.70-1.31], p = 0.78). Among wild-type KRAS patients, those with LC had significantly improved PFS when treated with cetuximab compared to BSC (median 5.4 versus 1.8 months, HR 0.28 [0.18-0.45], p < 0.0001), whereas those with RC did not (median 1.9 versus 1.9 months, HR 0.73 [0.42-1.27], p = 0.26), [interaction p = 0.002]. CONCLUSION: In refractory MCC, tumour location within the colon is not prognostic, but is strongly predictive of PFS benefit from cetuximab therapy. Additional research is needed to understand the molecular differences between RC and LC and their interaction with EGFR inhibition.

Performance of multinomial designs in comparison with response-based designs in non-randomized phase II trials of targeted cancer agents.

BACKGROUND: In phase II trials of cytotoxic agents, a multinomial phase II design incorporating early progression and response end points was shown to perform more efficiently than designs based only on response. We undertook a study to evaluate the performance of these designs in trials of targeted agents using the actual phase II data. PATIENTS AND METHODS: Using best response data from sequentially enrolled patients in 15 NCIC Clinical Trials Group and 7 European Organization for Research and Treatment of Cancer trials of targeted agents, we determined that trials would have been stopped at the end of stage I of accrual by applying rules generated by the multinomial and Fleming designs. Two variants of the multinomial design were studied: to stop accrual after stage I of enrolment, Variant A required either response or progression criteria to be met, whereas Variant B required that both response and progression criteria to be met. RESULTS: Using early progression, null/alternate hypotheses of 60% and 40% (60/40), the multinomial A variant recommended early stopping more often than the Fleming design. In most of the cases, this recommendation was correct given the final trial outcome. In contrast, the multinomial B variant never led to recommendations for early stopping and changing progression hypotheses did not improve the performance of this design. CONCLUSIONS: The multinomial A design using 60/40 hypotheses carried out better than the Fleming design in appropriately stopping trials of inactive targeted agents early. The multinomial B design was not useful for early stopping decisions. The multinomial A design may be favored over response-based designs in phase II trials of targeted agents.

Motion-guided attention promotes adaptive communications during social navigation.

Animals are capable of enhanced decision making through cooperation, whereby accurate decisions can occur quickly through decentralized consensus. These interactions often depend upon reliable social cues, which can result in highly coordinated activities in uncertain environments. Yet information within a crowd may be lost in translation, generating confusion and enhancing individual risk. As quantitative data detailing animal social interactions accumulate, the mechanisms enabling individuals to rapidly and accurately process competing social cues remain unresolved. Here, we model how motion-guided attention influences the exchange of visual information during social navigation. We also compare the performance of this mechanism to the hypothesis that robust social coordination requires individuals to numerically limit their attention to a set of n-nearest neighbours. While we find that such numerically limited attention does not generate robust social navigation across ecological contexts, several notable qualities arise from selective attention to motion cues. First, individuals can instantly become a local information hub when startled into action, without requiring changes in neighbour attention level. Second, individuals can circumvent speed-accuracy trade-offs by tuning their motion thresholds. In turn, these properties enable groups to collectively dampen or amplify social information. Lastly, the minority required to sway a group's short-term directional decisions can change substantially with social context. Our findings suggest that motion-guided attention is a fundamental and efficient mechanism underlying collaborative decision making during social navigation.

Collective motion in animal groups from a neurobiological perspective: the adaptive benefits of dynamic sensory loads and selective attention.

We explore mechanisms associated with collective animal motion by drawing on the neurobiological bases of sensory information processing and decision-making. The model uses simplified retinal processes to translate neighbor movement patterns into information through spatial signal integration and threshold responses. The structure provides a mechanism by which individuals can vary their sets of influential neighbors, a measure of an individual's sensory load. Sensory loads are correlated with group order and density, and we discuss their adaptive values in an ecological context. The model also provides a mechanism by which group members can identify, and rapidly respond to, novel visual stimuli.

Caregiving arrangement and nutrition: good news with some reservations.

The objective of this study was to assess the impact of caregiving arrangement on the iron and folate status of infants and toddlers reared at home or enrolled in centre-based, independent home, or licensed home care. One hundred and eighty-nine children aged 2 to 29 months were assessed 1 month prior to child care entry and at 6 months after entry into child care. Dietary (24-hour records), anthropometric (height, weight, head circumference) and biochemical (red blood cell folate, hematocrit, transferrin, and serum ferritin concentrations) methods were used to assess nutritional status. Frequency of illness was determined by a series of telephone interviews. Median intake of nutrients exceeded Canadian recommendations, regardless of care arrangement. Fifteen of 65 children had hematocrit values below age-specific cutoffs at the 6-month post-entry to child care visit. Children were frequently taken to obtain medical advice (average of 4 to 6 times during the study period) and 75% of subjects were prescribed at least one course of antibiotics. In conclusion, infants and toddlers in this study were generally well nourished, regardless of child care arrangement; however, iron status may remain an issue in this sample of infants and toddlers.

Comparison of Papanicolaou's and Wright-Giemsa stains in the examination of body fluids for Hodgkin's disease.

We reviewed 36 body fluid specimens from 18 patients with Hodgkin's disease (HD) to characterize the cytologic features of HD as seen in Wright-Giemsa (WG)-stained cytocentrifuge preparations, and to compare diagnostic agreement between WG- and Papanicolaou-stained samples. Slides were examined independently by two pathologists without knowledge of the original diagnosis, and were classified as either positive, inconclusive, or negative for malignant cells. There was diagnostic agreement between both methods in 35 (97%) of 36 samples. Features in cytocentrifuged WG-stained specimens that were most helpful in recognizing HD included mirror image nuclei in typical Reed-Sternberg cells and an axis of symmetry in polylobate Reed-Sternberg variants, with even distribution of the nuclear material within the cytoplasm.

Tumor-associated antigen expression of primary and metastatic colon carcinomas detected by monoclonal antibody 17-1A.

Murine monoclonal antibody (MAb) 17-1A has been used in radioimmunodetection and immunotherapy trials of intestinal adenocarcinoma in humans. Tumor heterogeneity of antigen expression has been recognized as a potential limiting factor in such studies. The authors report a study designed to evaluate the degree of heterogeneity of 17-1A antigen expression among primary and metastatic human colon carcinomas. All 141 specimens, including 74 primary or metastatic colonic adenocarcinomas, were evaluated with the use of an avidin-biotin complex immunoperoxidase technic on briefly fixed frozen tissue sections. All of these showed at least focal staining with MAb 17-1A. However, well- or moderately differentiated tumors generally showed diffuse cytoplasmic immunostaining, whereas poorly differentiated tumors showed minimal immunostaining with no detectable antigen in most areas. In 16 cases that had both primary and metastatic adenocarcinomas or multiple metastatic tumors, 17-1A antigen expression was similar among the tumor sites except for one case. This case showed variation in tumor differentiation and corresponding variation in 17-1A antigen expression. Of 36 additional malignant tumors that were not of colonic epithelial origin, adenocarcinomas of the stomach, duodenum, endometrium, ovary, and breast showed 17-1A antigen expression.

Polymicrobial bacteremic pneumonia: report of three cases caused by Staphylococcus aureus and Streptococcus pneumoniae.

Three patients are reported with simultaneous bacteremia caused by Staphylococcus aureus and Streptococcus pneumoniae complicating community-acquired pneumonia. Polymicrobial bacteremia caused by pyogenic organisms has rarely been reported. Two of the patients had severe underlying hepatic disease, and the third had suffered a recent myocardial infarction. The infection ultimately proved fatal in each patient. The pathophysiologic aspects and clinical consequences of polymicrobial bacteremia arising from respiratory as well as from other sources is briefly reviewed.

Pulmonary artery sarcomas. A review and report of a case.

We examined a case of primary pulmonary artery sarcoma and reviewed 45 cases that we found previously reported in the English literature, with particular attention given to the pathologic features. These sarcomas involve the pulmonary arterial trunk, left and right main pulmonary arteries, pulmonary valve, and right ventricular outflow tract. They have prominent intravascular growth along the arterial intima. Lung involvement commonly occurs by direct extension through the pulmonary vasculature or by distant metastases. These sarcomas contain a variety of heterologous components and areas of bone, cartilage, and fibrous tissue may be remarkably well-differentiated. Management of these sarcomas will be aided by an understanding of their biologic behavior and pathologic features.

Apical localization of pulmonary tuberculosis, chronic pulmonary histoplasmosis, and progressive massive fibrosis of the lung.

We have reviewed the accumulated evidence for the explanation of the apical localization of pulmonary tuberculosis, chronic pulmonary histoplasmosis, and massive fibrosis of the lung due to silicosis and coal-workers pneumoconiosis. The effect of gravity on the erect human lung results in greatly diminished pulmonary artery blood flow in the apical and subapical areas. This in turn results in higher oxygen tensions but also impairment of tissue clearance mechanisms in these areas. Analysis of the accumulated evidence better supports the theory of lymph stasis and impaired clearance of antigenic substances as the major determinant of the apical localization of pulmonary tuberculosis rather than the presently favored oxygen tension theory. The impaired clearance theory also best explains the apical localization of chronic pulmonary histoplasmosis and progressive massive fibrosis of the lung.

Histoplasmosis of bone.

A case of histoplasmosis of bone manifested by a single punched-out lesion in the humerus is reported in a man with asymptomatic mild chronic disseminated histoplasmosis. Roentgenologically evident lesions of bone due to Histoplasma capsulatum are rare, and this is the only report of a large punched-out lytic lesion. Such lesions are common in disseminated histoplasmosis due to the African strain H. duboisii. Although H. duboisii has been accorded species differentiation, there are only two clearly defined differences, compared to H. capsulatum. One is morphologic (size of yeast cell), and the other is a different clinical disease spectrum. Many believe that this organism is best viewed as a stable variant of H. capsulatum. At times, the two strains are indistinguishable morphologically, and at times, as in the case reported, there may be clinical similarities in their respective disease entities.

Chronic pulmonary histoplasmosis.

Chronic pulmonary histoplasmosis is best regarded as an opportunist or saprophytic infection of abnormal pulmonary spaces by a fungus of very low human pathogenicity. Tissue disease results from host immune response to dispersions of soluble antigen from these focal sources. There are two distinct types of clinical and radiological response. One is an acute or subacute illness manifested by often large segmental pneumonic lesions which tend to heal and are designated as early lesions. The other, usually developing as a complication of the first, is a chronic disease marked by persistent cavitation, low gard chronic illness, and a tendency to promote pulmonary fibrosis and often progressive pulmonary insufficiency. The early lesion is a segmental interstitial pneumonitis with central areas of infarct-like necrosis often adjacent to bullous disease and often outlining prominent emphysematous spaces which appear as radiolucencies. These radiological findings are further characterized by early clearing of the interstitial components, infarct-like contraction of the necrotic zones, obliteration of much of the contained emphysematous and bullous spaces, and healing attended by considerable loss of lung volume. Symptoms are variable but tend to be mild. Malaise, fatigability, low-grade fever, aching chest pain and mild cough lasting a few days to a few weeks are usual. Symptoms are ameliorated by rest. Rest and diminished activity are recommended as treatment. Under these circumstances, 80% of early lesions heal completely and probably most of these would heal spontaneously. Any subsequent course of the disease depends on whether or nor large air spaces, adjacent to or contained within the area of pneumonitis, become infected and persist as cavities. This occurs in 20% of early lesions. Once established, an infected cavity tends to persist and to be attended by symptoms of chronic bronchitis with chronic cough and sputum, fatigability, anorexia, and weight loss. Persisting thickwalled cavities often induce gradual development of pulmonary fibrosis, particulary in the lung bases, apparently from aspiration of antigenic material. This and the accelerated obstructive bronchopulmonary disease often lead to progressive pulmonary insufficiency. The use of amphotericin B is recommended for all persistent thick-walled cavities and in some circumstances surgical resection may be indicated.