A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer

The standard de Gramont (dG) regimen of fortnightly leucovorin, bolus fluorouracil and 22-h infusion of fluorouracil, d1+2, and the same regimen plus oxaliplatin, are effective but also cumbersome. We therefore present simplified ‘Modified de Gramont’ (MdG) regimens. Forty-six advanced gastrointestinal cancer patients entered a dose-exploring study of MdG, including an expanded cohort of colorectal cancer patients at optimum dose. Treatment (fortnightly) comprised: 2-h i.v.i. leucovorin (350 mg d,l-LV or 175 mg l-LV, not adjusted for patient surface area); bolus fluorouracil (400 mg m−2), then ambulatory 46-h fluorouracil infusion (2000–3600 mg m−2, cohort escalation). Subsequently, 62 colorectal patients (25 unpretreated; 37 fluorouracil-resistant) received MdG plus oxaliplatin (OxMdG) 85 mg m−2. Fluorouracil pharmacokinetics during MdG were compared with dG. The optimum fluorouracil doses for MdG alone were determined as 400 mg m−2 bolus + 2800 mg m−2 46-h infusion. A lower dose of 400 mg m−2 bolus + 2400 mg m−2 infusion which, like dG produces minimal toxicity, was chosen for the OxMdG combination. Fluorouracil exposure (AUC0–48 h) at this lower dose is equivalent to dG. With OxMdG, grade 3–4 toxicity was rare (neutropenia 2.8% cycles; vomiting or diarrhoea <1% cycles), but despite this there were two infection-associated deaths. Oxaliplatin was omitted for cumulative neurotoxicity in 17 out of 62 patients. Objective responses in colorectal cancer patients were: 1st-line MdG (22 assessable): PR=36%, NC=32%, PD=32%. 1st-line OxMdG (24 assessable): CR/PR=72%; NC=20%; PD=8%; 2nd line OxMdG (34 assessable): PR=12%; NC=38%; PD=50%. MdG and OxMdG are convenient and well-tolerated. OxMdG was particularly active as 1st-line treatment of advanced colorectal cancer. Both regimens are being further evaluated in the current UK MRC phase III trial

Splenic size after division of the short gastric vessels in Nissen fundoplication in children

Item does not contain fulltextPURPOSE: Nissen fundoplication is an effective treatment for gastro-esophageal reflux disease (GERD). Mobilization of the gastric fundus during fundoplication requires division of short gastric vessels of the spleen, which may cause splenic ischemia. The aim of this study was to determine if Nissen fundoplication results in hypotrophy of the spleen. METHODS: We performed pre-operative and post-operative ultrasound measurements of the spleen in children undergoing Nissen fundoplication. During operation, the surgeon estimated the compromised blood flow by assessment of the percentage of discoloration of the spleen. RESULTS: Twenty-four consecutive children were analyzed. Discoloration of the upper pole of the spleen was observed in 11 patients (48%) of a median estimated splenic surface of 20% (range 5-50%). The median ratio for pre-operative and post-operative length, width, and area of the spleen was 0.97, 1.03, and 0.96, respectively. The percentage of the estimated perfusion defect during surgery was not correlated with the ratios. In three patients, the area ratio was smaller than 0.8 (0.67-0.75), meaning that the area decreased with at least 20% after surgery. In none of these patients a discoloration was observed. CONCLUSION: Discoloration of the spleen after Nissen fundoplication is not associated with post-operative splenic atrophy.1 maart 201

An Alternate STAT6-Independent Pathway Promotes Eosinophil Influx into Blood during Allergic Airway Inflammation

Enhanced eosinophil responses have critical roles in the development of allergic diseases. IL-5 regulates the maturation, migration and survival of eosinophils, and IL-5 and eotaxins mediate the trafficking and activation of eosinophils in inflamed tissues. CD4⁺ Th2 cells are the main producers of IL-5 and other cells such as NK also release this cytokine. Although multiple signalling pathways may be involved, STAT6 critically regulates the differentiation and cytokine production of Th2 cells and the expression of eotaxins. Nevertheless, the mechanisms that mediate different parts of the eosinophilic inflammatory process in different tissues in allergic airway diseases remain unclear. Furthermore, the mechanisms at play may vary depending on the context of inflammation and microenvironment of the involved tissues. We employed a model of allergic airway disease in wild type and STAT6-deficient mice to explore the roles of STAT6 and IL-5 in the development of eosinophilic inflammation in this context. Quantitative PCR and ELISA were used to examine IL-5, eotaxins levels in serum and lungs. Eosinophils in lung, peripheral blood and bone marrow were characterized by morphological properties. CD4⁺ T cell and NK cells were identified by flow cytometry. Antibodies were used to deplete CD4⁺ and NK cells. We showed that STAT6 is indispensible for eosinophilic lung inflammation and the induction of eotaxin-1 and -2 during allergic airway inflammation. In the absence of these chemokines eosinophils are not attracted into lung and accumulate in peripheral blood. We also demonstrate the existence of an alternate STAT6-independent pathway of IL-5 production by CD4⁺ and NK cells that mediates the development of eosinophils in bone marrow and their subsequent movement into the circulation

Diffusion of Subsidized ACTs in Accredited Drug Shops in Tanzania: Determinants of Stocking and Characteristics of Early and Late Adopters.

Many households in sub-Saharan Africa utilize the private sector as a primary source of treatment for malaria episodes. Expanding access to effective treatment in private drug shops may help reduce incidence of severe disease and mortality. This research leveraged a longitudinal survey of stocking of subsidized artemisinin combination therapies (ACTs), an effective anti-malarial, in Accredited Drug Dispensing Outlets (ADDOs) in two regions of Tanzania. This provided a unique opportunity to explore shop and market level determinants of product diffusion in a developing country retail market. 356 ADDOs in the Rukwa and Mtwara regions of Tanzania were surveyed at seven points between Feb 2011 and May 2012. Shop level audits were used to measure the availability of subsidized ACTs at each shop. Data on market and shop level factors were collected during the survey and also extracted from GIS layers. Regression and network based methodologies were used. Shops classified as early and late adopters, following Rogers' model of product diffusion, were compared. The Bass model of product diffusion was applied to determine whether shops stocked ACTs out of a need to imitate market competitors or a desire to satisfy customer needs. Following the introduction of a subsidy for ACTs, stocking increased from 12% to nearly 80% over the seven survey rounds. Stocking was influenced by higher numbers of proximal shops and clinics, larger customer traffic and the presence of a licensed pharmacist. Early adopters were characterized by a larger percentage of customers seeking care for malaria, a larger catchment and sourcing from specific wholesalers/suppliers. The Bass model of product diffusion indicated that shops were adopting products in response to competitor behavior, rather than customer demand. Decisions to stock new pharmaceutical products in Tanzanian ADDOs are influenced by a combination of factors related to both market competition and customer demand, but are particularly influenced by the behavior of competing shops. Efforts to expand access to new pharmaceutical products in developing country markets could benefit from initial targeting of high profile shops in competitive markets and wholesale suppliers to encourage faster product diffusion across all drug retailers

Neurogenic bladder: etiology and assessment

A review of the various causes of neurologic impairment to the lower urinary tract in children was the aim of this presentation. The emphasis was on diagnosis, pathophysiology, and treatment that strive to maintain as normal a function as possible in order to achieve eventual urinary continence and health of the upper urinary tract. The latest principles based on the most up to date evidence are promulgated but with an eye towards historical prospective. The reader should gain an adequate understanding of various disorders that comprise this condition and feel comfortable with proposing options for management when faced with the responsibility of caring for an affected child

Treatment in advanced colorectal cancer: what, when and how?

Treatment of advanced colorectal cancer (CRC) increasingly requires a multidisciplinary approach and multiple treatment options add to the complexity of clinical decision-making. Recently novel targeted therapy against angiogenesis and epidermal growth factor receptor completed a plethora of phase III studies. The addition of bevacizumab to chemotherapy improved the efficacy over chemotherapy alone in both first and second line settings, although the magnitude of benefit may not be as great when a more optimal chemotherapy platform is used. Studies performed thus far did not address conclusively whether bevacizumab should be continued in subsequent lines of treatment. Anti-angiogenesis tyrosine kinase inhibitors have not shown any additional benefit over chemotherapy alone so far. Although some benefits were seen with cetuximab in all settings of treating advanced CRC, K-ras mutation status provides an important determinant of who would not benefit from such a treatment. Caution should be exercised in combining anti-angiogenesis with anti-EGFR strategy until further randomised data become available. In this review, we have focused on the implications of these trial results on the everyday management decisions of treating advanced CRC

Ethnicity and sexuality

This paper explores the connections between ethnicity and sexuality. Racial, ethnic, and national boundaries are also sexual boundaries. The borderlands dividing racial, ethnic, and national identities and communities constitute ethnosexual frontiers, erotic intersections that are heavily patrolled, policed, and protected, yet regularly are penetrated by individuals forging sexual links with ethnic "others." Normative heterosexuality is a central component of racial, ethnic, and nationalist ideologies; both adherence to and deviation from approved sexual identities and behaviors define and reinforce racial, ethnic, and nationalist regimes. To illustrate the ethnicity/sexuality nexus and to show the utility of revealing this intimate bond for understanding ethnic relations, I review constructionist models of ethnicity and sexuality in the social sciences and humanities, and I discuss ethnosexual boundary processes in several historical and contemporary settings: the sexual policing of nationalism, sexual aspects of US-American Indian relations, and the sexualization of the black-white color line