BACCHUS: A randomised non-comparative phase II study of neoadjuvant chemotherapy (NACT) in patients with locally advanced rectal cancer (LARC).

BACKGROUND: Chemoradiation (CRT) or short-course radiotherapy (SCRT) are standard treatments for locally advanced rectal cancer (LARC). We evaluated the efficacy/safety of two neoadjuvant chemotherapy (NACT) regimens as an alternative prior to total mesorectal excision (TME). METHODS/DESIGN: This multi-centre, phase II trial in patients with magnetic resonance imaging (MRI) defined high-risk LARC (>cT3b, cN2+ or extramural venous invasion) randomised patients (1:1) to FOLFOX + Bevacizumab (Arm 1) or FOLFOXIRI + bevacizumab (Arm 2) every 14 days for 6 cycles prior to surgery. Patients were withdrawn if positron emission tomography (PET) standardised uptake value (SUV) after 3 cycles failed to decrease by >30% or increased compared to baseline. Primary endpoint was pathological complete response rate (pCR). Secondary endpoints included adverse events (AE) and toxicity. Neoadjuvant rectal (NAR) scores based on "T" and "N" downstaging were calculated. FINDINGS: Twenty patients aged 18-75 years were randomised. The trial stopped early because of poor accrual. Seventeen patients completed all 6 cycles of NACT. One stopped due to myocardial infarction, 1 poor response on PET (both received CRT) and 1 committed suicide. 11 patients had G3 AE, 1 G4 AE (neutropenia), and 1 G5 (suicide). pCR (the primary endpoint) was 0/10 for Arm 1 and 2/10 for Arm 2 i.e. 2/20 (10%) overall. Median NAR score was 14·9 with 5 (28%), 7 (39%), and 6 (33%) having low, intermediate, or high scores. Surgical morbidity was acceptable (1/18 wound infection, no anastomotic leak/pelvic sepsis/fistulae). The 24-month progression-free survival rate was 75% (95% CI: 60%-85%). INTERPRETATION: The primary endpoint (pCR rate) was not met. However, FOLFOXIRI and bevacizumab achieved promising pCR rates, low NAR scores and was well-tolerated. This regimen is suitable for testing as the novel arm against current standards of SCRT and/or CRT in a future trial.

Bevacizumab and Combination Chemotherapy in rectal cancer Until Surgery (BACCHUS): a phase II, multicentre, open-label, randomised study of neoadjuvant chemotherapy alone in patients with high-risk cancer of the rectum.

BACKGROUND: In locally advanced rectal cancer (LARC) preoperative chemoradiation (CRT) is the standard of care, but the risk of local recurrence is low with good quality total mesorectal excision (TME), although many still develop metastatic disease. Current challenges in treating rectal cancer include the development of effective organ-preserving approaches and the prevention of subsequent metastatic disease. Neoadjuvant systemic chemotherapy (NACT) alone may reduce local and systemic recurrences, and may be more effective than postoperative treatments which often have poor compliance. Investigation of intensified NACT is warranted to improve outcomes for patients with LARC. The objective is to evaluate feasibility and efficacy of a four-drug regimen containing bevacizumab prior to surgical resection. METHODS/DESIGN: This is a multi-centre, randomized phase II trial. Eligible patients must have histologically confirmed LARC with distal part of the tumour 4-12 cm from anal verge, no metastases, and poor prognostic features on pelvic MRI. Sixty patients will be randomly assigned in a 1:1 ratio to receive folinic acid + flurourcil + oxaliplatin (FOLFOX) + bevacizumab (BVZ) or FOLFOX + irinotecan (FOLFOXIRI) + BVZ, given in 2 weekly cycles for up to 6 cycles prior to TME. Patients stop treatment if they fail to respond after 3 cycles (defined as ≥ 30 % decrease in Standardised Uptake Value (SUV) compared to baseline PET/CT). The primary endpoint is pathological complete response rate. Secondary endpoints include objective response rate, MRI tumour regression grade, involved circumferential resection margin rate, T and N stage downstaging, progression-free survival, disease-free survival, overall survival, local control, 1-year colostomy rate, acute toxicity, compliance to chemotherapy. DISCUSSION: In LARC, a neoadjuvant chemotherapy regimen - if feasible, effective and tolerable would be suitable for testing as the novel arm against the current standards of short course preoperative radiotherapy (SCPRT) and/or fluorouracil (5FU)-based CRT in a future randomised phase III trial. TRIAL REGISTRATION: Clinical trial identifier BACCHUS: NCT01650428.

Recommendations for influenza and pneumococcal vaccinations in people receiving chemotherapy.

There is some uncertainty among oncologists about the safety and efficacy of immunising people undergoing chemotherapy against influenza and Streptococcus pneumoniae. This paper aims to summarise current information about this subject and provide recommendations for immunising this patient group.

Dietary intake, eating behavior, and physical activity-related determinants of high body mass index in rural communities in Wyoming, Montana, and Idaho.

OBJECTIVE: To assess the relation between body mass index (BMI) levels and various lifestyle variables related to physical activity and specific characteristics of a healthy eating pattern, using baseline cross-sectional data from the Wellness IN the Rockies project. SUBJECTS: A total of 928 males and 889 females, aged 18-99 y, recruited from six rural communities in Wyoming, Montana, and Idaho. MEASUREMENTS: Using BMI as the criterion, overweight was defined as a BMI >or=25 kg/m(2) and obesity was defined as a BMI >or=30 kg/m(2). All participants in this study completed a questionnaire that elicited sociodemographic information, self-reported height and weight, and data related to specific dietary intakes, eating-related behaviors, and physical activity behaviors and perceptions. RESULTS: Prevalence of overweight was 70% in men and 59% in women. Increased likelihood of overweight or obesity was associated with greater frequency of the following: drinking sweetened beverages such as soft drinks/soda pop, ordering supersized portions, eating while doing other activities, and watching television. Other predictors were lower frequency of participation in physical activity and the perception of not getting as much exercise as needed. CONCLUSIONS: The increased probability of having a high BMI in individuals who more often eat while doing another activity appears to be a novel finding that will need to be substantiated by additional research. The finding that the vast majority of overweight and obese respondents believed that they do not get as much exercise as needed strengthens the assertion that finding ways to increase participation in physical activity should remain a high priority in obesity prevention and intervention efforts at the community and individual levels.

Discovery of inhibitors of cell adhesion molecule expression in human endothelial cells. 1. Selective inhibition of ICAM-1 and E-selectin expression.

A critical early event in the inflammatory cascade is the induced expression of cell adhesion molecules on the lumenal surface of vascular endothelial cells. These adhesion molecules include E-selectin, ICAM-1, and VCAM-1, which serve to recruit circulating leukocytes to the site of the inflammation. These adhesive interactions allow the leukocytes to firmly adhere to and cross the vascular endothelium and migrate to the site of tissue injury. Pharmaceutical agents which would prevent the induced expression of one or more of the cell adhesion molecules on the endothelium might be expected to provide a novel mechanism to attenuate the inflammatory responses associated with chronic inflammatory diseases. A thieno[2,3-d]pyrimidine, A-155918, was identified from a whole-cell high-throughput assay for compounds which inhibited the tumor necrosis factor-alpha (TNFalpha)-induced expression of E-selectin, ICAM-1, or VCAM-1 on human vascular endothelial cells. Traditional medicinal chemistry methods were applied to this low-micromolar inhibitor, resulting in the 2,4-disubstituted thieno[2,3-c]pyridine A-205804, a potent and selective lead inhibitor of E-selectin and ICAM-1 expression (IC(50) = 20 and 25 nM, respectively). The relative position of the nitrogen atom in the thienopyridine isomer was shown to be critical for activity, as was a small amide 2-substituent.

Synthesis and structure-activity relationships of 2-pyridones: a novel series of potent DNA gyrase inhibitors as antibacterial agents.

Two novel series of 2-pyridones were synthesized by transposition of the nitrogen of 4-quinolones to the bridgehead position. This subtle interchange of the nitrogen atom with a carbon atom yielded two novel heterocyclic nuclei, pyrido[1,2-alpha]pyrimidine and quinolizine, which had not previously been evaluated as antibacterial agents and were found to be potent inhibitors of DNA gyrase. Quinolizines with a methyl group at the 9-position such as (S)-45a (ABT-719) demonstrate exceptional broad spectrum antibacterial activity. Most notably, they are active against resistant bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant strains of enterococci, and ciprofloxacin-resistant organisms. In addition, 2-pyridones also possess favorable physiochemical and pharmacokinetic properties. These 2-pyridones were synthesized from the commercially available starting materials by 10-17 linear transformations. The structure of an adduct yielded by this sequence, (S)-45a (ABT-719), was determined by X-ray crystallographic analysis.

Redox glycosidation: the use of Nozaki-Takai methylenylation in a highly stereoselective synthesis of sucrose.

Sequential reaction of 2,3,4,6-tetra-O-benzyl-D-glucopyranose (7) with butyllithium and 2-[2,3,5-tri-O-benzyl-4-O-(tert-butyldiphenylsilyl)-D- arabinonoyl]thio-3-nitropyridine (6) at -78 degrees gave 2,3,4,6-tetra-O-benzyl-alpha-D-glucopyranosyl 2,3,5-tri-O-benzyl-4-O-(tert-butyldiphenylsilyl)-D-arabinonate+ ++ (8; 71%, alpha:beta greater than 50:1). Ester carbonyl methylenylation, desilylation, and iodoetherification in the presence of silica gave 3,4,6-tri-O-benzyl-1-deoxy-1-iodo-(2,3,4,6-tetra-O-benzyl-alpha-D- glucopyranosyl)-beta-D-fructofuranoside (15; 44%, alpha:beta greater than 50:1). This neopentylic iodide 15 was converted into sucrose (1;80%) by free-radical substitution using TEMPO (24) followed by sodium-ammonia reduction, acetylation, and Zemplén methanolysis.

A comparative economic analysis of work-related hypertension care programs.

Cost of care and blood pressure control achieved were examined for individuals enrolled in two worksite hypertension control programs. In the first program, care was provided in a community-based setting by private physicians (model I-CBC); in the second program care was rendered by nurses under the supervision of a physician in work-based clinics (model II-WBC). In both situations, however, identification of employees with hypertension was effected through screening at the worksite. After adjustment for differences in labor market costs, annual average costs per client were found to be comparable for both programs. Blood pressure control (less than 160/95 mm Hg) was greater in model II-WBC than in model I-CBC. The average cost per unit of blood pressure reduction achieved by model II-WBC was +8.25 compared with +28.84 for model I-CBC, indicating a greater cost-effectiveness for worksite care programs.

Increased excretion of urinary N-acetyl-beta-glucosaminidase in essential hypertension and its decline with antihypertensive therapy.

The urinary excretion of N-acetyl-beta-glucosaminidase (NAG) is increased in patients whose renal function is impaired by a variety of kidney diseases, and may provide an index of renal injury. To assess its role in essential hypertension, we measured urinary levels of NAG in 80 subjects with essential hypertension (and no evidence of renal disease) and 30 normal controls. NAG values were measured before therapy and after 3 and 12 months of treatment with diuretics. The mean urinary NAG value (+/- S.D.) for the normotensive subjects was 29 +/- 16 nmol per hour per milligram of urinary creatinine. The median value for the untreated hypertensive subjects was 53, and the mean was 65 +/- 61 (P less than 0.01). Systolic blood pressure was directly correlated with NAG levels, whereas diastolic pressure, age, sex, and race were not. Eighty patients followed for one year attained their ultimate blood-pressure reduction within three months (from a mean of 158/103 mm Hg to one of 138/91 mm Hg; P less than 0.001), whereas the urinary NAG level had not declined significantly at three months (from 60 +/- 43 to 54 +/- 54) but had changed significantly at one year (to 45 +/- 28; P less than 0.01 as compared with the initial value). These data suggest that NAG is frequently elevated in patients with high blood pressure even though there is no other evidence of renal damage, and that it can be reduced by successful antihypertensive therapy.

Fraud in science.

KIE: Instances of research fraud such as the John Darsee case have raised questions about the incidence of fraud in scientific research and the willingness of the biomedical establishment to acknowledge and correct the problem. There is no consensus among scientists and editors of medical journals about how widespread data falsification is, whether it can be identified and controlled through the traditional peer review process, and whether or not it should be a matter of public concern. The authors conclude that fraud in science is a complex issue which requires more attention from researchers, administrators, and editors than it now receives.^ieng

Occupationally-sponsored, community-provided hypertension control.

A hypertension control program established by the Massachusetts Mutual Life Insurance Company in 1977 included education, on-site case finding, and referral to community physicians with a company-based follow-up system facilitated by assumption of all costs by the company. Ninety-eight percent (2, 463) of the employees were screened; 11% (277) had hypertension. Of these, 59% were in treatment and 36% were controlled at entry. More than 84% of the hypertensives accepted referral to care and 79% fulfilled all program requirements. By the fifth program years, 70% had achieved blood pressure control. Mean blood pressure declined from 150/93 to 142/88 mm Hg. Absenteeism for all hypertensives averaged 4.7 in the three years before and 5.7 during the four years of the program. Employees active in the program had fewer average days of absenteeism (4.7) than inactive participants (6.8). Modest cost and a favorable employee/physician response has made this a highly acceptable as well as an effective company health program.

Absenteeism and labelling in hypertensive subjects. Prevention of an adverse impact in those at high risk.

In this work-site population, the illness absenteeism of 259 hypertensive subjects was studied in the year after they were screened and labelled. Absenteeism due to illness increased more in 48 patients who were unaware of their hypertension (newly labelled) than in the 211 subjects who were aware. Among the newly labelled subjects, only the young subjects and those with "pure" systolic hypertension experienced increased absenteeism; the older subjects with diastolic hypertension did not. The newly labelled subjects who received active follow-up and treatment with antihypertensive medication had only minimal increases in absenteeism. In contrast, those who received active follow-up without medication, and those who received only episodic follow-up had significantly greater increases. Vigorous efforts are warranted to insure active follow-up and treatment for hypertensive subjects after their condition has been labelled. Caution should be exercised in labelling, however, if no antihypertensive treatment is initiated.

A company-instituted program to improve blood pressure control in primary care.

An occupation-based effort to improve the outcome of antihypertensive therapy provided in the community was instituted by the Massachusetts Mutual Life Insurance Company in 1977. The goal of the program was to utilize the administrative and organizational resources of the company to enhance employee/patient adherence to treatment provided in conventional primary care settings. Key elements of the program were: companywide education and on-site screening, referral to community physicians and company assumption of all patient costs, linked to a monitoring system to permit oversight of care. Initially, 98% of employees were screened, 70% accepted referral for care and 59% fully adhered to program performance criteria. Blood pressure control has risen from 36% at the beginning to 69% at the end of the second year. Fully compliant patients have achieved the greatest lowering of blood pressure and compiled the best work attendance record. Program costs are modest and acceptance by employees and physicians supports the concept that occupation-based, systematic efforts can enhance the impact of primary care.