A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

Background:

Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies.

Patients and Methods:

Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients'' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload.

Results:

A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival.

Conclusions:

Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.     

Dosimetric implications of the addition of 18 fluorodeoxyglucose-positron emission tomography in CT-based radiotherapy planning for non-small-cell lung cancer

The aim of this study was to assess the impact of F-18 fluorodeoxyglucose-positron emission tomography (FDG-PET) CT on radiotherapy planning parameters for patients treated curatively with radiotherapy for non-small-cell lung cancer (NSCLC). Five patients with stages I–III NSCLC underwent a diagnostic FDG-PET CT (dPET CT), planning FDG-PET CT (pPET CT) and a simulation CT (RTP CT). For each patient, three radiation oncologists delineated a gross tumour volume based on RTP CT alone, and fused with dPET CT and pPET CT. Standard expansions were used to generate PTVs, and a 3D conformal plan was created. Normal tissue doses were compared between plans. Coverage of pPET CT PTV by the plans based on RTP CT and dPET CT was assessed, and tumour control probabilities were calculated. Mean PTV was similar between RTP CT, dPET CT and pPET CT, although there were significant inter-observer differences in four patients. The plans, however, showed no significant differences in doses to lung, oesophagus, heart or spinal cord. The RTP CT plan and dPET CT plan significantly underdosed the pPET PTV in two patients with minimum doses ranging from 12 to 63% of prescribed dose. Coverage by the 95% isodose was suboptimal in these patients, but this did not translate into poorer tumour control probability. The effect of fused FDG-PET varied between observers. The addition of dPET and pPET did not significantly change the radiotherapy planning parameters. Although FDG-PET is of benefit in tumour delineation, its effect on normal tissue complication probability and tumour control probability cannot be predicted.     

新型缓释辅料甲壳胺的研究 Ⅱ甲壳胺对不同性质药物的适应性的研究

目的：考察甲壳胺对不同性质药物的适应性。方法：选择了盐酸麻黄碱,盐酸心得安,卡马西平,磺胺嘧啶,阿司匹林,法莫替丁,朴热息痛,潘生丁,茶碱,炎痛喜康,水杨酸等不同性质的１１种药物,以甲胺为阻滞剂,制备了缓释型骨架片溶出效果。结果：甲壳胺的缓释作用随药物碱性增强,分子量增大,溶解度降低而增强,结论：甲 胺对不同性质的药物均有一定缓释作用。     

Induced drug resistance inhibits selection of initiated cells and cancer development

Compounds exerting a mitoinhibitory effect on normal hepatocytes are potent promoters in the resistant hepatocyte model of chemical carcinogenesis in combination with stimulation of regenerative growth by partial hepatectomy or treatment with carbon tetrachloride. 2- Acetylaminofluorene (2-AAF) almost completely inhibits liver cell regeneration after partial hepatectomy, allowing only resistant cells to participate in regenerative growth. After initiation by diethylnitrosamine and promotion with 2-AAF and partial hepatectomy (PH), focal growth of initiated cells generates liver lesions which occupy 40% of the hepatic volume three weeks after PH. In this work the mechanism for the anti promoting effects of phenobarbital and 3- methylcholantrene were investigated as well as their effects on the development of malignant hepatocellular carcinoma in the resistant hepatocyte model. Treatment with phenobarbital or, especially, 3- methylcholanthrene rendered normal rat hepatocytes resistant to the mitoinhibitory effect of 2-AAF. In combination with 2-AAF/PH, 3- methylcholanthrene shortened the regenerative growth period to less than one week. In the Solt-Farber protocol for experimental hepatocarcinogenesis, treatment with phenobarbital or 3- methylcholanthrene during promotion with 2-AAF/PH permitted hepatocytes surrounding the focal lesions to respond with regenerative growth. The foci and surrounding liver grew until the liver/body mass index reached the control value. With phenobarbital treatment the total focal volume was 20% of the liver volume three weeks after PH, whereas the corresponding value in the case of 3-methylcholanthrene was only 1%. Labelling index data supported the conclusion that growth of the liver lesions in the resistant hepatocyte model was dependent on differential inhibition of normal hepatocyte growth by the promoter and that the size of the foci obtained was related to the length of time after PH required to complete liver regeneration. 3-methylcholanthrene induced 2- AAF resistance prevented the development of large persistent nodules and hepatocellular carcinoma while phenobarbital delayed cancer development with several month. The data thus supports the idea that the degree of clonal expansion during promotion determines the size of the population at risk for malignant transformation, as well as the final frequency of carcinomas.      

氯屈膦酸二钠合成工艺改进

目的：对氯屈膦酸二钠的合成工艺进行了研究。方法：以二溴甲烷和亚膦酸三异丙酯为原料,经缩合,氯化,热裂解和成盐反应得到氯屈膦酸二钠。结果：合成产物的化学结构经元素分析,红外光谱,质谱和核磁共振谱确证,总收率为60．3％。结论：此合成路线是完全可行的。     

Malignant phaeochromocytoma and hypercalcaemia.

We describe a case of hypercalcaemia secondary to recurrent malignant phaeochromocytoma. Parathyroid-related protein (PTHrp 1-86) immunoreactivity was identified in plasma and PTHrp was identified by immunocytochemistry in tumour tissue.     

Screening for asymptomatic carriage of Trichophyton tonsurans in household contacts of patients with tinea capitis: results of 209 patients from South London

BACKGROUND: There is currently an epidemic of tinea capitis in urban areas of developed countries caused by Trichophyton tonsurans. Recurrence or re-infection with dermatophyte is not uncommon after adequate oral treatment. Asymptomatic carriers who are household contacts may partly explain this observation by forming a reservoir for infection. PATIENTS/METHODS: Two-hundred and nine household contacts of patients with tinea capitis were examined and screened for asymptomatic carriage of dermatophyte. RESULTS: Only 7.2% had clinically evident disease yet 44.5% had silent fungal carriage on the scalp. Children under 16 years were much more likely to be carriers than adults (P < 0.001) and males were less likely than females to be affected (P < 0.01). CONCLUSION: This evidence poses questions about factors relevant in transmission of dermatophytes. The authors propose that all household contacts of patients with tinea capitis should be offered screening to eradicate a potential reservoir of infection.     

Collection of pluripotential hematopoietic stem cells by cytapheresis

Successful complete hematopoietic reconstitution (CHR) using nonleukemic peripheral stem cells (PSC) after marrow ablation has been reported in animals but not man. Previous studies of cytapheresis products from humans, as a prelude to use for CHR, have documented the presence of committed myeloid (CFU-GM) and erythroid (BFU-E) precursors. We have examined mononuclear cell (MNC) products collected on the Fenwal CS3000 Blood Cell Separator for these plus the more primitive mixed (granulo-, erythro-, mono-, and megakaryocytic) cell colony-forming units (CFU-GEMM) and for various lymphocytic subpopulations (LSP). One to two-hour products contained 36 +/- 7 CFU- GEMM/10(6) MNC (mean +/- SE, n = 8) or 490 +/- 131/ml product. This compared favorably with blood (23 +/- .4/10(6) MNC or 46 +/- 8/ml, n = 14) and bone marrow (146 +/- 58/10(6) MNC, n = 12). Collection efficiency for E-rosette-positive cells approximated that for total lymphocytes and was variable for other LSP. Recovery of CFU-GEMM after freezing in 10% dimethylsulfoxide at a controlled rate and storage in liquid N2 was 54% +/- 8% (n = 8). Cytapheresis collection of large numbers of pluripotent hematopoietic precursors and demonstration of adequate recovery of these after cryopreservation, both previously unreported, are significant steps toward eventual CHR using nonleukemic PSC.     

Two case reports of perineal hernia after laparoscopic abdominoperineal resection with a proposed modification to the operative technique

Perineal hernia is a rare complication following laparoscopic abdominoperineal resection (APR) for rectal cancer. We present two case reports of perineal hernia following laparoscopic APR and discuss their management. We suggest that they developed because the pelvic peritoneum was left open during laparoscopic APR and propose that closure of the pelvic peritoneum should be routine in this operation.