Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative.

BACKGROUND: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. MATERIAL AND METHODS: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. RESULTS: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. CONCLUSION: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting.

[A simple functional diagnostic test. The isotope nephrogram]. / Un test de dépistage fonctionnel simple. Le néphrogramme isotopique.

Developed daily in our urological consultation the conventional O.I.H. renogram assesses the vascular, tubular and interstitial renal function and the outflow of the kidneys and ureters cavities. The dose of irradiation is extremely low. Ecological advantages associated to a very low cost price and keen informations put this functional test to a first place in the urological technical screen.

[Changes in intrinsic autonomic innervation in congenital or primary megabladder]. / Altérations de l'innervation neurovégétative intrinsèque dans les mégavessies congénitales ou primaires.

In eleven non-diabetic women suffering from high compliance bladder, the authors correlate urodynamic findings with the modifications of the autonomic vesical innervation. Endoscopic biopsies show a dramatic reduction in acetylcholinesterase-positive innervation in the detrusor but less visible in the trigone. The adrenergic network density is also reduced in both areas, according to age. Congenital conditions, high pressure mechanisms, vascular hypoxia explain these autonomic alterations inducing iatrogenic problems associated with different drug treatments. In some cases, urethral hypertonic instability acts in the same way as mechanical obstruction.

[Modifications in spermatogenesis following antibiotic therapy]. / Modifications de la spermatogénèse après antibiothérapie.

Among eleven antibiotics with a high activity on the mitosis and on the meiosis of the seminal cells, gentamycin sulfate and cefuroxime are both the most aggressive. After 8, 15 or 30 days of treatment, a stop of the mitosis and of the meiosis, pyknosis and karyolysis are morphologically visualized in male adult rats. Histoenzymatic studies show first a decrease of the protein synthesis in the nuclei of the spermatogonia and of the spermatocytes, and second a decrease of the glucose metabolism in the spermatocytes layers. In other groups of rats treated, the sacrifice was performed after arrest of antibiotics, the morphological recuperation is slow after 8 days of treatment, none after 15 or 30 days. Histoenzymatic studies show that the recuperation of the protein metabolism is quicker than the glucose one. Arising after 8 days it can be complete after 15 to 30 days of rest. Some coincidences between these experimental works and some clinical disturbances in the fertility of men and animals after high doses of antibiotic may be pointed out.

[Levator muscles pf the anus (levator ani). Normal or pathological cytoarchitecture of endorectal biopsies in man]. / Muscles releveurs de l'anus (levator ani) cytoarchitecture normale ou pathologique prélèvements endorectaux chez l'homme.

The structure and ultrastructure of normal or pathological needle biopsies of the human levator ani are studied. Disturbances of the muscular cyto-architecture: cellular degeneration with infiltration of glycogen and disorganization of the myofibrillar A, I and Z stripes are shown. The comparison between the histological data and the clinical results demonstrates that the quality of the levator ani is not always clearly defined by the clinic. The muscular biopsy reaches its main interest when in physical reeducation or in surgical correction of the incontinence, some doubt remains on the clinical value of the levator ani.

[Reflux pneumonephrosis in a case of vesicorectal fistula]. / Pneumonéphrose par reflux dans un cas de fistule vésicorectale.

Pneumonephrosis is extremely rare. In most of the cases, it is due to a fistula between the high urinary tract and the bowel. We report a case of pneumonephrosis, due to a fistula between the bladder and the rectum, accompanied by vesico-ureteral reflux, with ascent of the air into the ureter and the kidney.

[Determination of the activity of extracts of Echinaceae and Sabal in the treatment of idiopathic megabladder in women]. / Mesure de l'activité des extraits d'Echinaceae et de Sabal dans le traitement des mégavessies idiopathiques chez la femme.

30 patients (25 to 76 years old), suffering from incontinence (18), pollakiuria (6) and dysuria (6) reveal at the urodynamic investigation (urovideo 2100 and neuromatic 2000M) an idiopathic large hypotonic bladder. 20 have been treated by Echinaceae (84 to 112 mg/a day) and sabalae (78 to 104 mg/a day) extracts (URGENIN: 90 to 120 drops/a day) during a mean time of 77 days. 10 have received 90 to 120 drops/a day of a placebo during a mean time of 52 days. The statistical evaluations have been carried on accord the STUDENT test for small numbers corrected by the FISHER factor. After placebo no modification of the symptomatology and no significant difference in the measures have been registered. After Urgenin: the bladder capacity, the residual urine and the compliance are significantly decreased; the detrusor pressure and the peak flow are significantly increased. The uretral pressure, the closure pressure and the uretral instability show a non-significant decrease. The modifications of the profilometers and sphincter EMG are not significant. In two cases bilateral vesico-renal refluxes have disappeared. The results of the study suggest that the neurotransmission is facilitated and that the smooth muscle fiber is activated by URGENIN. They measure the positive activity of Echinaceae and Sabalae extracts in the treatment of female idiopathic large hypotonic bladders.

[Evaluation of the density of acetylcholinesterase-positive and intrinsic adrenergic innervation of the uterus in rats]. / Evaluation de la densité de l'innervation acétylcholinestérase-positive et adrénergique intrinsèque de l'utérus chez le rat.

According to the Karnovsky and Roots modified by E1 Badawi and Schenk's technique for the acetylcholinesterase-positive innervation and according to the Lindvall and Björklund modified by de la Torre and Surgeon's method for the adrenergic one, we have demonstrated the nervous fibers in the different tissues of the cervix, the corpus and the cornu of the she-rat in pro-oestrus. A statistic evaluation of the density of these nervous networks has been established for the different regions. The study of the histograms demonstrates the predominance of acetylcholinesterase-positive innervation versus the adrenergic one. The evolution of the nervous densities is similar for each tissue in the corpus and the cornu, these of the myometrium are the highest. In the cervix, the acetylcholinesterase-positive fibers dominate over the mucosal and submucosal ones, on the other hand, the adrenergic ones are richest in the muscle. Our morphometric studies confirm statistically the optic observations of the others authors.

[Morphometry of sacral neurons innervating the pelvic muscles. Experimental study]. / Morphométrie des noyaux sacrés innervant les muscles pelviens. Etude expérimentale.

Sacral motoneurons of the pelvic muscles have been extensively studied in the rat (1,2). Few informations occur in the literature on their specific morphology and their interconnection. In an experimental study we have differentiated the neuronal mapping of the: bulbo-spongiosus (B.S.M.), ischio-cavernosus (I.C.M.), levator ani (L.A.M.), sphincter ani (S.A.M.) and sphincter urethrae (S.U.M.) muscles. Each different or both sided pelvic muscle of 30 wistar rats have been injected by a solution of horse-radish-peroxidase. Using this H.R.P. technique, the mapping of the marked neurons and compared to the different muscles has been performed on horizontal and transversal spinal cord sections. A statistical study using the "T" test compares the maximal and minimal diameters and the surface of the neurons. 1. Most of the muscles injected in one side left or right receive their innervation from the neurons located in the homolateral side of the spinal cord. 2. The B.S.M. and the S.A.M. receive, in part, an innervation from the opposite side. 3. The neurons of the B.S.M. and of the S.A.M. are located in the D.M. group of L5 - L6 segment of the spinal cord. Their diameters are significantly different but not their surfaces (+/- 940 mu 2). 4. The neurons of the I.C.M. and of the S.U.M. located in the D.L. group have an equivalent diameter and surface. 5. The neurons of the L.A.M. have the largest diameter but an equivalent surface to the others. This work on a mammalian model brings further informations on the mapping of the sacral innervation of the pelvic muscles and offers a comparative reference for Man.

[Cholinergic and adrenergic innervation of the bladder obstructed by urethral stenosis in the rat]. / L'innervation cholinergique et adrénergique de la vessie obstruée par sténose de l'urètre chez le rat.

In the obstructed bladder by urethral stenosis the morphometry studies show a decrease of the cholinergic and adrenergic intrinsic innervation in a different way according the tissue layer and the experimental delay. Adrenergic nerves are more affected than cholinergic ones but they recover more quickly. In the adventitia and the sub-mucosa first affected by the high pressures inside the bladder the density of the autonomous nerves decreases from the first week. The perivascular and muscular nervous fibers are less sensitive and the similar shape of their innervation histogram gives evidence of a tight bond between their adrenergic network. Beside their motor participation the adrenergic terminal fibers may play a role in the cellular trophicity of the muscle.

[Ultrastructural modifications of the bladder wall in senescence]. / Modifications ultrastructurales de la paroi vésicale au cours de la sénescence.

Histochemical and ultrastructural studies of the epithelial, muscular, connective, vascular and nervous tissue layers have been carried on endoscopic or surgical biopsies in patients from 23 to 92 years old. Beyond 70 years old, the junctional complexes between the superficial cells of the epithelium are altered and the number of intracellular organelles is diminished. The intercellular spaces and binds between the muscle cells are modified. Some interstitial fibrosis occurs and the density of the connective tissue increases. The authors describe also similar observation in the bladder wall of the old rats. An arteriosclerosis of small vessels is observed. The density of the autonomous nervous network is reduced and the cholinergic innervation becomes preponderant. No specific ultrastructural modification of the nerves is seen except a neuromuscular infiltration by a conjunctive hyperplastic tissue. These morphological changes can be related to some modifications of the vesical compliance.