Rheology of human faeces and pathophysiology of defaecation.

BACKGROUND: Rectal evacuation involves multiple mechanisms that are not completely understood. The aim of this study was to quantify the rheologic property, i.e., yield stress, which governs the ease of deformation of a range of faeces of differing consistency and understand its influence on the pathophysiology of defaecation. METHODS: Yield stresses of faeces of differing consistencies and Bristol scores were determined by the Vane test. We then explored the effects of this property on ease of defecation using a simple static model of the recto-anal junction based on the laws of flow for yield stress pastes and checked the conclusions by X-ray defaecography experience. RESULTS: The yield stress of faeces increased exponentially with their solid content, from 20 to 8000 Pa. The static model of the recto-anal junction showed that evacuation of faeces of normal consistency and yield stress is possible with moderate dilatation of the anal canal, whilst the evacuation of faeces with higher yield stress requires greater dilatation of the anal canal. X-ray defaecography showed that such increases occurred in vivo. CONCLUSIONS: The diameter of the recto-anal junction is increased to enable the passage of feces with high yield stress. The finite limits to such dilation likely contribute to fecal impaction. Hence, difficulties in defaecation may result either from unduly high yield stress or pathologies of reflex recto-anal dilatation or a combination of the two.

Short term memory properties of sensory neural architectures.

A functional role of the cerebral cortex is to form and hold representations of the sensory world for behavioral purposes. This is achieved by a sheet of neurons, organized in modules called cortical columns, that receives inputs in a peculiar manner, with only a few neurons driven by sensory inputs through thalamic projections, and a vast majority of neurons receiving mainly cortical inputs. How should cortical modules be organized, with respect to sensory inputs, in order for the cortex to efficiently hold sensory representations in memory? To address this question we investigate the memory performance of trees of recurrent networks (TRN) that are composed of recurrent networks, modeling cortical columns, connected with each others through a tree-shaped feed-forward backbone of connections, with sensory stimuli injected at the root of the tree. On these sensory architectures two types of short-term memory (STM) mechanisms can be implemented, STM via transient dynamics on the feed-forward tree, and STM via reverberating activity on the recurrent connectivity inside modules. We derive equations describing the dynamics of such networks, which allow us to thoroughly explore the space of possible architectures and quantify their memory performance. By varying the divergence ratio of the tree, we show that serial architectures, where sensory inputs are successively processed in different modules, are better suited to implement STM via transient dynamics, while parallel architectures, where sensory inputs are simultaneously processed by all modules, are better suited to implement STM via reverberating dynamics.

[Lung cancer screening with low-dose thoracic CT-scan in the Somme area]. / Dépistage des cancers bronchopulmonaires par tomodensitométrie thoracique à faible dose dans la Somme.

RATIONALE: This feasibility trial proposes to set up in the department of the Somme an annual screening for lung cancer with low-dose thoracic CT. It responds to the first objective of the third cancer plan and follows the publication of the results of the National Lung Screening Trial in 2011. METHODS: The method of this study is to use the existing networks among and between healthcare professionals and the departmental cancer screening structure. The inclusion criteria will be those of the National Lung Screening Trial. Screening will be proposed by treating physicians and chest physicians. The CT-scan will be performed in radiological centers that adhere to the good practice charter for low radiation scanning. A copy of CT results will be sent to the departmental structure of cancer screening (ADEMA80) which will ensure traceability and will perform statistical analysis. The study received funding from the Agence régionale de santé de la Picardie and la ligue contre le cancer. EXPECTED RESULTS: The primary endpoints of this screening will be the number of cancers diagnosed and the survival of the patients. The follow-up of positive examinations, delays in management and the level of participation will also be assessed.

Dynamic cystocolpoproctography is superior to functional pelvic MRI in the diagnosis of posterior pelvic floor disorders: results of a prospective study.

AIM: The accuracy of dynamic cystocolpoproctography (DCP) and dynamic MRI were compared in diagnosing posterior pelvic floor disorders. METHOD: Fifty consecutive female patients (mean age 51 years) complaining of posterior compartment pelvic floor disorder and referred to a tertiary centre entered the prospective study. The Institutional Review Board stated that informed consent from the patients was not necessary for this study. Patients underwent a DCP and a supine functional MRI by two different radiologists. Assessment of radiological examinations was prospective and blind. All patients underwent surgery that led to the final diagnosis. Agreement between the operative diagnosis and the diagnoses following DCP and MRI was assessed using the weighted kappa statistic. A matched-pairs McNemar's test was applied to demonstrate whether or not one radiological method was superior to the other. RESULTS: Full-thickness rectal prolapse was best diagnosed by clinical examination. Internal rectal prolapse and peritoneocele were best diagnosed by DCP. A better agreement with the operative diagnosis, which is not true superiority, was observed for DCP compared with functional pelvic MRI for full-thickness rectal prolapse, internal rectal prolapse and peritoneocele. There was no significant difference between DCP and functional pelvic MRI in the diagnosis of internal rectal prolapse (P = 0.125) or peritoneocele (P = 0.10). CONCLUSION: As full-thickness rectal prolapse, internal rectal prolapse and peritoneocele might be missed by functional pelvic MRI, there should still be a place for DCP in particular cases where the clinical diagnosis is not clear in women with symptomatic posterior pelvic floor disorders.

Bone mass density, subsequent risk of colon cancer and survival in postmenopausal women.

OBJECTIVES: To test the hypothesis that high bone mass density (BMD), a potential marker for cumulative exposure to endogenous estrogen, calcium and vitamin D intake, is associated with a lower risk of colon cancer, and that women with a lower BMD are likely to develop a more aggressive form of colon cancer, as defined by mortality. STUDY DESIGN AND SETTING: BMD was measured in three different sites (Ward's triangle, trochanter, femoral neck) in 1,471 women 60 years of age. All incident cases of colon cancers were identified through record-linkage of cancer registry. The women were followed for a mean of 9.5 years. RESULTS: Overall 31 cases of colon cancer were observed among 28.6 expected (standardized incidence ratio (SIR) = 1.09, 95% confidence interval: 0.79-1.25). The SIR decreased with increasing BMD showing a significantly decreasing risk of 20% for women who were at the higher BMD comparatively to women who were at the lower BMD in all the skeletal sites. The 10-year survival rates showed that survival was increasing with increased BMD, but not significantly. CONCLUSION: The findings suggest that postmenopausal women with lower BMD have an increased risk of colon cancer. The biological mechanisms linking bone mass to colon cancer risk are not clear.

Therapeutic management of laryngeal cancer. Results of a study of 356 patients from the Cancer Registry of the Somme, France.

CONCLUSIONS: The global survival rate was low compared to those reported in the literature, in which the analyzed populations were selected according to the tumor stage or treatment. This study should be prolonged and should also involve other cancer registries in France in order to increase the number of patients and to analyze tumors of comparable stage and therapeutic management. OBJECTIVE: To analyze the survival rate of a non-selected laryngeal cancer population from the Cancer Registry of the Somme, a French region. MATERIAL AND METHODS: A total of 356 patients were included in a retrospective study covering the period 1987-1997. Survival and prognostic factors were analyzed. Statistical analysis was performed using the Kaplan-Meier method, the Cox model and the chi2 test. RESULTS: The 5-year global survival rate was 42% for males and 55% for females. Tumor localization, T, N and M stages and surgery were found to be significant prognostic factors. Sex and age were not statistically significant factors. For stage I tumors, surgery alone gave better results than radiotherapy alone in terms of global survival. No difference occurred in terms of local recurrence. A similar comparison was not possible for stage II-IV tumors owing to the small number of cases.

Influence of abnormal screens on delays and prognostic indicators of screen-detected breast carcinoma.

BACKGROUND: Delay to diagnosis following an abnormal screening result is associated with morbidity such as anxiety, but its effect on prognosis is unknown. METHODS: Using data from the Somme area breast cancer screening programme (France), we identified 29,511 women aged 50-69 years who underwent screening between 1996 and 2000. We prospectively followed women with an abnormal screening result until completion of the assessment process and evaluated the effect of delay to notification, diagnosis and treatment on prognostic indicators. RESULTS: Women with high-suspicion screens (n=976) compared with those with intermediate-suspicion screens (n=1008) were investigated more promptly, presented larger tumours (62% vs 42%, p=0.03), and were more likely to be lymph node positive (36% vs 17%, p=0.02). Compared with a delay to diagnosis 6 months. Similarly, a 1.4-fold and 2-fold increased risk of lymph node involvement was observed for delays of >3 to 6 months, respectively, compared with the reference interval. CONCLUSION: The authors' findings suggest that women with high-suspicion mammograms were investigated more promptly, and that delays to diagnosis of asymptomatic breast carcinoma >6 months were associated with progression of the cancer measured by tumour size >10 mm and lymph node metastasis.

[Gynecological and breast cancer in the department of Somme]. / Cancers gynécologiques et mammaires dans le département de la Somme.

BACKGROUND: Breast and gynecological tumors are the most common cancers in women. The aim of this study was to show the epidemiologic features of gynecological and breast cancers in the French administrative district of La Somme. METHODS: This study focused on the 1982-1999 period. Incidence, mortality and survival rates were calculated. RESULTS: In 1997-1999, the world standardized breast incidence and mortality rates were 81.6 and 20.2 per 100,000 females per year. Breast and genital tract cancers accounted for 47% of all cancers in women. The incidence and mortality of uterine cervix cancers showed a clear decline over the past 10 years, whereas the trend of breast cancers was dominated by continuing increase. However, mortality was stable for breast cancers. Five year relative survival rates were respectively 80% for breast cancers, and 68%, 76%, 38%, for uterine cervix, uterine body and ovary cancers respectively. Incidence and mortality rates in Somme were in the middle risk range of other cancer French registries. CONCLUSION: The results of this study indicate that genital tract and breast cancers constitute a serious public health problem pointing out the importance of screening activities in the Somme area.

Molecular mechanisms underlying the interaction between ZD1839 ('Iressa') and cisplatin/5-fluorouracil.

ZD1839 ('Iressa'), an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is currently being investigated in clinical trials as a treatment for cancer. 'Iressa' is a trademark of the AstraZeneca group of companies. We have previously demonstrated a synergistic interaction between ZD1839 and cisplatin/5-fluorouracil (5FU) in CAL33, a human head and neck cancer cell line that markedly expresses EGFR. This study examined the effects of this drug combination on the cell cycle, cell cycle regulators, apoptosis-related factors, EGFR-related signalling and DNA repair in CAL33 cells. The cells were incubated with ZD1839 alone for 48 h, then cisplatin and 5FU were added. Exposure to the drug combination continued for a further 48 h. ZD1839 alone induced accumulation of cells in the G0/G1 phase of the cell cycle at 24 h accompanied by a concomitant increase in p21, p27 and Bax, a significant decrease in Bcl2 and a decrease in Akt phosphorylation. A decrease in DNA-PK was observed at 48 h. ZD1839 alone had no effect on caspase-3 activity, but addition of ZD1839 to cisplatin-5FU led to a significant increase in caspase-3 activity at 96 h. Thus, ZD1839 affects key cellular pathways controlling cell proliferation, apoptosis and DNA repair. These data provide a rationale to support clinical trials combining ZD1839 and cisplatin-5FU and other protocols that combine EGFR-targeting agents with chemotherapy or radiotherapy.

Evaluation of an algorithm to identify incident breast cancer cases using DRGs data.

Hospital databases have the potential to be inexpensive, timely and nationally representative sources of information about cancer. This study examines the utility of the French hospital database adapted from the Diagnosis Related Group (DRG) classification and named 'Programme de médicalisation des systèmes d'information (PMSI)', as an independent source to identify incident cancer cases. From the 19 679 women hospitalized and treated in 1998 in the public hospitals of the Somme area in France, we identified those diagnosed with breast cancer in the PMSI database. These women were matched with women in the cancer registry of the Somme area who had been diagnosed with breast cancer in 1998. An algorithm was used to identify cancer-related diagnoses and procedures reported to PMSI. The sensitivity, specificity and positive predictive value (PPV) of the PMSI database were calculated using the cancer registry as a gold standard. The PMSI database had 85% sensitivity, 99.9% specificity and 97% PPV for women hospitalized with breast cancer as a principal diagnosis. The sensitivity was higher by 9% for hospitalization with breast cancer as a secondary diagnosis but had a lower PPV (78%). In conclusion, the PMSI database seems to offer an interesting potential to assess breast cancer incidence, because of its high sensitivity, in particular when secondary diagnosis was considered, and its very high specificity and PPV. However, these preliminary results need to be confirmed by other studies in France before such databases are used, particularly in areas without cancer registries.

[Incidence and prevalence estimations for breast and colorectal cancer in the Picardy region]. / Estimation de l'incidence et de la prévalence du cancer du sein et du cancer colorectal dans la région de Picardie.

OBJECTIVES: To provide incidence and prevalence data on breast and colorectal cancer in the Picardie area of France. METHODS: An age-period-cohort method was used to estimate regional incidence and prevalence of cancer from regional cancer mortality data and patient survival data recorded in the Somme Cancer Registry. RESULTS: European standardized breast incidence for 1998 was 110 per 100000 inhabitants. The incidence for colorectal cancer was 67 per 100000 for men and 47 per 100000 for women. Prevalence was 9656 for breast cancer and 6283 (2941 for men and 3342 for women) for colorectal cancer. Incidence of breast cancer increased considerably (80.9%) between 1979 and 1998. CONCLUSION: These results provide data on breast cancer and colorectal cancer which are useful for planning demand for healthcare or medical surveillance in the Picardie area.

Influence of epidermal growth factor receptor (EGFR), p53 and intrinsic MAP kinase pathway status of tumour cells on the antiproliferative effect of ZD1839 ("Iressa").

of ZD1839 ("Iressa") is an orally active, selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), which blocks signal transduction pathways implicated in proliferation and survival of cancer cells, and other host-dependent processes promoting cancer growth. Permanent downstream activation of the mitogen-activated protein kinase pathway can theoretically bypass the upstream block of epidermal growth factor receptor-dependent mitogen-activated protein kinase activation at the epidermal growth factor receptor level. We investigated the impact of epidermal growth factor receptor content, p53 status and mitogen-activated protein kinase signalling status on ZD1839 sensitivity in a panel of human tumour cell lines: seven head and neck cancer cell lines and two colon cancer cell lines (LoVo, HT29) with derivatives differing only by a specific modification in p53 status (LoVo p53 wt + p53 mut cells, HT29 p53 mut + p53 wt rescued cells). The antiproliferative activity of ZD1839 was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide test. ZD1839 concentrations ranged from 0.2-200 microM (48 h exposure). Epidermal growth factor receptor expression, p53 status and p42/p44 (for testing a constitutively active mitogen-activated protein kinase pathway status) were determined by competition analysis (Scatchard plots), denaturing gradient cell electrophoresis and Western blot, respectively. Epidermal growth factor receptor levels ranged from 388 to 33794 fmol mg(-1) protein, a range that is similar to that found in head and neck tumours. The IC(50) values for cell sensitivity to ZD1839 ranged from 6 to 31 microM and a significant inverse correlation (P=0.022, r=0.82) between IC(50) values and epidermal growth factor receptor levels was observed. There was no influence of p53 status on the sensitivity to ZD1839. In two head and neck cancer cell lines with comparably elevated epidermal growth factor receptor expression, a two-fold higher ZD1839 IC(50) value was found for the one with a constitutively active mitogen-activated protein kinase. In conclusion, ZD1839 was active against cells with a range of epidermal growth factor receptor levels, although more so in cells with higher epidermal growth factor receptor expression. Activity was unaffected by p53 status, but was reduced in cells strongly dependent on epidermal growth factor receptor signalling in the presence of an intrinsically activated mitogen-activated protein kinase pathway.

Sequence-dependent effects of ZD1839 ('Iressa') in combination with cytotoxic treatment in human head and neck cancer.

Elevated levels of epidermal growth factor receptor in head and neck cancer have been extensively reported, and are correlated with poor prognosis. The combination of cisplatin and 5-fluorouracil is a standard treatment regimen for head and neck cancer, with radiation representing another therapeutic option. Six head and neck cancer cell lines were used to study the cytotoxic effects of combining ZD1839 ('Iressa'), a new selective epidermal growth factor receptor tyrosine kinase inhibitor, and radiation. Two of the cell lines were also used to study the combination of ZD1839 and cisplatin/5-fluorouracil. Cytotoxic effects were assessed by the MTT test. The results indicated that ZD1839 applied before radiation gave the best effects (P=0.002); an effect that was strongest in those p53-mutated cell lines that express the highest epidermal growth factor receptor levels. The effects of ZD1839 with cisplatin and/or 5-fluorouracil were sequence dependent (P<0.003), with the best results achieved when ZD1839 was applied first. For the triple combinations, ZD1839 applied before cisplatin and 5-fluorouracil resulted in a slight synergistic effect (P=0.03), although the effect was greater when ZD1839 was applied both before and during cytotoxic drug exposure. In conclusion, ZD1839 applied before radiation and before and/or during cisplatin/5-fluorouracil may improve the efficacy of treatment for head and neck cancer.

Impact of thymidine phosphorylase surexpression on fluoropyrimidine activity and on tumour angiogenesis.

Tumoral thymidine phosphorylase (TP) appears to play a dual role by being involved in neoangiogenesis and by activating 5FU prodrugs at the tumoral target site. The aim of the study was to investigate more thoroughly these potential physiological and pharmacological roles of TP. A rat carcinoma cell line (PROb) was transfected with TP/PD-ECGF in order to study the effect of the overexpression of this enzyme (1) on the sensitivity of cells to 5'DFUR and 5FU in vitro and (2) on tumour growth in vivo by using a syngenic tumour model in the BDIX rat (hepatic tumours, sub-cutaneous tumours). Cytotoxic effects of 5'DFUR, and to a lesser extent those of 5FU, were enhanced in TP clones as compared to control cells: there was a highly significant correlation between TP activity and in vitro sensitivity to 5'DFUR (r2= 0.91, P = 0.0002, n = 8) and, to a lesser extent, to 5FU (r2= 0.49, P = 0.053, n = 8). The impact of TP transfection on tumour growth was relatively modest and concerned only the initial stages of tumour expansion. Staining of TP tumours for endothelial (factor VIII) cells was always higher than controls. The staining ratio (TP/controls) tended to be reduced as tumours increased in size. The stability of TP expression was checked both in vitro (TP activity measurement) and in vivo (RT-PCR determinations) and there was no loss of TP expression over time which could be advanced to explain the progressive weakening of the impact of TP overexpression on both tumour growth and neoangiogenesis.

Interval cancers in a French breast cancer-screening programme (Somme Department).

The objective of this study is to analyse the detection rates and tumour diameter of interval cancers in the breast cancer mass-screening programme of Somme Department (France), launched in 1990. Interval cancers are defined as breast cancers diagnosed within 36 months after a negative screening assessment, for women attending the programme between December 1990 to December 1993. Age-adjusted incidence rates were 0.51 per 1000 woman-years of follow-up in the 3-year interval after initial and subsequent screens. Diagnosis is made at early stage (sizes < or = 10 mm) in 20% of interval cancers. This stage is higher than that in screened women (9% of in situ cases and 35% of very small tumours). Interval cancer rates are low during the first year (0.18 per 1000 woman-years of follow-up) but higher in the second and third years.

Alcohol consumption by non-institutionalised elderly women: the EPIDOS Study.

The prevalence of alcohol use declines with age, but studies suggest that between 2% and 4% of the elderly population have a particularly high alcohol consumption. The objective of this study was to verify or refute this finding and identify clinical or social characteristics associated with alcohol consumption. We measured alcohol consumption by autoquestionnaire in 7575 women, aged 75 or older, recruited at five centers in France. The alcohol consumption was computed taking account of the number of beer, wine or liquor (or spirits) drinks consumed per day. The mean age of the respondents was 80+/-6 y. Forty percent used some alcohol and 2.5% drank more than 30 grams per day. Smoking, good health status, higher socioeconomic status or single marital status were factors whose percentages increased significantly with increasing alcohol use. Despite the advanced age of this population, regular alcohol intake was prevalent but not heavy and abusive consumption drinking. Drinking appears to be associated with some medical or social characteristics and possibly with better health status.

Ternary combination of irinotecan, fluorouracil-folinic acid and oxaliplatin: results on human colon cancer cell lines.

A marked antitumour efficacy is currently obtained by oxaliplatin (LOHP)-fluorouracil (FU)-folinic acid (FA) combination and by CPT11-FU-FA combination. Logically, the triple association LOHP, CPT11 and FUFA will be soon tested in cancer patients. The aim of the present study was to compare two schedules combining SN38 (the active metabolite of CPT11, irinotecan) with FU-FA and LOHP. The two schedules differed by the SN38 position. The relative contribution of each drug in the resulting global cytotoxicity was evaluated. Two human colon cancer cell lines were used (WIDR and SW620 both p53 mutated). LOHP plus FA were applied for 2 h, just before a 48 h FU exposure. The SN38 sequence was applied for 24 h, starting either 48 h before LOHP-FA (schedule A), or just after LOHP-FA exposure (schedule B). Cytotoxicity was assessed by the 3-(4,5-demethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) test and drug interactions were analysed according to the Chou and Talalay method, based on the computation of a combination index (CI). The SN38 position significantly induces a shift from additivity-antagonism when SN38 was applied after LOHP, towards additivity-synergism when SN38 was applied first (P = 0.03). The relative contribution (RC) of each drug in the overall cytotoxicity of the triple combination was defined as the drug concentration giving 50% cell lethality (IC(50)) of the double association without that drug divided by the IC(50)of the triple association. Whatever the SN38 position, the larger contribution was made by LOHP (median RC = 2.4) and the smaller by SN38 (median RC = 1.1). In addition, the contribution of FUFA was improved when SN38 was applied first (median RC = 2.2) as compared to the opposite schedule (median RC = 1.2). Results were in agreement between the two explored cell lines. The present data should be taken into account when establishing the rationale of future trials combining CPT11, LOHP and FU-FA.

High bone-mass density as a marker for breast cancer in post-menopausal women.

Bone mass has been proposed as a marker of cumulative exposure to oestrogen in women. We have studied the association between bone mass and breast cancer in postmenopausal women. In 126 cases of breast cancers and 126 controls, the bone mineral density (BMD) of the lumbar spine (L2-L4), femoral neck, trochanter and Ward's triangle was measured by dual-energy X-ray absorptiometry. All cases of cancer were confirmed by pathological reports. A questionnaire including information on reproductive history and other variables was collected. BMD was significantly higher among breast cancer patients than controls at all sites, except at the femoral neck where BMD was increased in the cancer group, but not significantly. After adjustment for potential confounding factors, the estimated relative risk of breast cancer in the highest quartile of BMD compared to the lowest quartile ranged from 2.5 to 4.8 for various sites of measurement. These results confirm that bone-mass density is a strong predictor for breast cancer in postmenopausal women. Women in the lowest quartile of bone mass appear to be protected against breast cancer. The mechanisms underlying this relation may be explained by cumulative exposure to oestrogen.

Rectal akinesia as a new cause of impaired defecation.

PURPOSE: The aim of this prospective study was to point out a new concept of dyschezia using dynamic videoproctography. METHODS: A total of 154 consecutive patients with impaired defecation prospectively underwent dynamic videoproctography from 1996 to 1998. Evacuation of thick barium of standardized consistency was fully videotaped under fluoroscopy in the sitting position. We measured the weight of barium injected into the rectum (Q1 in g), the weight of barium evacuated (Q2 in g) and the time for rectal evacuation (t in seconds). Flow rate and postdefecation residue were given by calculating Q2/t and (Q1 - Q2) X 100/Q1, respectively. We studied all patients whose flow rate and postdefecation residue were less than 5 g/second and more than 30 percent, respectively. These values were arbitrarily chosen, based on rectal evacuation in 25 controls (5 healthy volunteers together with 20 patients without dyschesia). RESULTS: Nine of 154 patients with dyschesia fulfilled the criteria and had none of the usually known causes of dyschezia, such as anismus, megarectum, intussusception, rectal prolapse, rectocele, or enterocele. These nine patients had a normal rectal anatomic appearance and a wide-open short anus but despite exhausting straining efforts were unable to obtain total rectal emptying. Dynamic videoproctography brings strong arguments for an absence of rectal wall contraction, despite normal functioning pelvic floor. CONCLUSIONS: Dynamic videoproctography allows identification of new features in patients with dyschesia: very slow defecation flow rate and high postdefecation residue. This new concept could be called rectal akinesia by analogy with bladder akinesia in some dysuric patients.