Search

Additional file 4: Changes from baseline in primary and secondary iNPH scale scores for the PP population.

Additional file 1: Home exercises.

Additional file 2: INPH scale decription.

Additional file 3: Changes from baseline in primary and secondary iNPH scale scores for the ITT population.

Gleason grading specified in ISUP 2014 is the clinical standard in staging prostate cancer and the most important part of the treatment decision. However, the grading is subjective and suffers from high intra and inter-user variability. To improve the consistency and objectivity in the grading, we introduced glandular tissue WithOut Basal cells (WOB) as the ground truth. The presence of basal cells is the most accepted biomarker for benign glandular tissue and the absence of basal cells is a strong indicator of acinar prostatic adenocarcinoma, the most common form of prostate cancer. Glandular tissue can objectively be assessed as WOB or not WOB by using specific immunostaining for glandular tissue (Cytokeratin 8/18) and for basal cells (Cytokeratin 5/6 + p63). Even more, WOB allowed us to develop a semi-automated data generation pipeline to speed up the tremendously time consuming and expensive process of annotating whole slide images by pathologists. We generated 295 prostatectomy images exhaustively annotated with WOB. Then we used our Deep Learning Framework, which achieved the $2^{nd}$ best reported score in Camelyon17 Challenge, to train networks for segmenting WOB in needle biopsies. Evaluation of the model on 63 needle biopsies showed promising results which were improved further by finetuning the model on 118 biopsies annotated with WOB, achieving F1-score of 0.80 and Precision-Recall AUC of 0.89 at the pixel-level. Then we compared the performance of the model against 17 biopsies annotated independently by 3 pathologists using only H\&E staining. The comparison demonstrated that the model performed on a par with the pathologists. Finally, the model detected and accurately outlined existing WOB areas in two biopsies incorrectly annotated as totally WOB-free biopsies by three pathologists and in one biopsy by two pathologists., Accepted as oral presentation at Medical Imaging with Deep Learning (MIDL) 2019, July, London, England

BACKGROUND Although there is evidence for a reduction in breast carcinoma mortality with mammographic screening, some doubts have been expressed, and there is still uncertainty regarding the age specific effects. METHODS The authors report on a randomized, controlled trial of mammographic screening for breast carcinoma that was conducted among 51,611 women (21,650 women who were invited to a screening [the study group] and 29,961 women in a control group) ages 39–59 years in Gothenburg, Sweden. Among women in the study group, the screening interval was 18 months. The screening phase of the trial took place in 1982–1991, and follow-up for breast carcinoma mortality continued until December 31, 1996. Mortality from breast carcinoma was analyzed using a Poisson regression model. Overall and age specific effects of invitation to mammography screening on breast carcinoma mortality were calculated. Three mortality effects were estimated: the effect on deaths from breast tumors diagnosed during the screening phase of the trial, as assessed by an independent Endpoint Committee (the EPC evaluation model); the effect on deaths from breast carcinoma diagnosed during the screening phase of the trial, as determined by data from the National Cancer Registry and the National Cause of Death Register (the SCB evaluation model); and the effect on deaths from all breast carcinomas diagnosed up to December 31, 1996, as determined by the National Cancer Registry and the National Cause of Death Register (the SCB follow-up model). RESULTS A nonsignificant, 21% reduction in the rate of mortality from breast carcinoma with invitation to screening was observed using the EPC evaluation model (relative risk [RR], 0.79; 95% confidence interval [95% CI], 0.58–1.08; P = 0.14); and a borderline significant, 23% rate reduction was observed using the SCB follow-up model (RR, 0.77; 95% CI, 0.60–1.00; P = 0.05). Age specific analyses yielded greater mortality rate reductions for the groups of women ages 39–44 years, 45–49 years, and 55–59 years, but there was no mortality rate reduction in the group of women ages 50–54 years. The effects of invitation to mammographic screening on the incidence of lymph node-positive disease closely paralleled the effects of invitation on breast carcinoma mortality. The effect on breast carcinoma mortality was consistent with the effect on all-cause mortality, suggesting no bias in classification of cause of death. Breast carcinoma incidence in the study group was almost identical to the incidence in the control group after trial by screening had ended in the control group (RR, 0.98; 95% CI, 0.88–1.09; P = 0.7). CONCLUSIONS The current results support the commonly observed 20–30% reduction in breast carcinoma mortality with invitation to screening. The impression that screening is less effective in women younger than 50 years may be an oversimplification. Age specific effects should be a target for further research. Cancer 2003;10:2387–96. © 2003 American Cancer Society. DOI 10.1002/cncr.11361

H. W. Reesink, S. Panzer, C. A. Gonzalez, N. Lena, P. Muntaabski, S. Gimbatti, E. Wood, M. Lambermont, V. Deneys, D. Sondag, T. Alport, D. Towns, D. Devine, P. Turek, M.-K. Auvinen, T. Koski, C. K. Lin, C. K. Lee, W. C. Tsoi, E. Lawlor, G. Grazzini, V. Piccinini, L. Catalano, S. Pupella, H. Kato, S. Takamoto, H. Okazaki, I. Hamaguchi, J. C. Wiersum-Osselton, A. J. W. van Tilborgh, P. Y. Zijlker-Jansen, K. M. Mangundap, M. R. Schipperus, D. Dinesh, P. Flanagan, O. Flesland, C. T. Steinsvag, A. Espinosa, M. Letowska, A. Rosiek, J. Antoniewicz-Papis, E. Lachert, M. B. C. Koh, R. Alcantara, M. Corral Alonso & E. Muniz-Diaz

Methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX) plasma concentration-time curves (AUC) have been analyzed in 24 patients after different routes of MTX administration. After an i.v. bolus (50 mg/m2), the AUC for 7-OH-MTX is correlated with that for MTX and inversely correlated with the MTX plasma clearance. When MTX is administered with plasma steady level standardization, using the test-dose protocol, at a level of 10(-5) M over 36 hr (10(-5), 36 hr), 7-OH-MTX-AUC is still correlated with the i.v. bolus pharmacokinetic parameters. The dose prediction using the classical test-dose protocol provides a less efficient MTX dose adjustment at 5 X 10(-4) M over 8 hr (5.10(-4), 8 hr) and the hydroxylation process is no more correlated with the i.v. parameters. On the opposite, upon 6 successive infusions with 10(-5), 36 hr or 5.10(-4), 8 hr protocols, the plasma concentrations of 7-OH-MTX are not significantly modified. This suggests that the hydroxylation process is not inducible.

Uptake characteristics of Cyclosporine A (CsA), an immunosuppressive agent widely used in organ transplantation, have been evaluated in RAJI cells, a human Burkitt lymphoma cell line which (i) does not bear T-cell markers, (ii) is insensitive to CsA after a 1 hr exposure to concentrations up to 50 micrograms/ml, and (iii) does not metabolize CsA. CsA is rapidly accumulated inside the cells until a near steady-state is achieved (within 1-3 min). This uptake is characterized by two components: one linear process saturable at low drug concentrations (lower than 1 microgram/ml) and another not saturable component even at high drug concentrations (up to 50 micrograms/ml). Uptake of CsA is temperature-dependent and unaffected by the presence of CsD, a structural CsA analog (50 micrograms/ml CsD) or sodium azide (10 mM) in the extracellular compartment. Intracellular accumulation of CsA is associated with the rapid appearance of a cytosolic drug-protein complex, which is responsible at least in part, for the large amount of total drug accumulated inside the cells. Chromatographic analysis of this (3H)CsA-macromolecule complex on a Bio-Gel P-60 exclusion column demonstrates that the molecular weight of this protein(s), likely cyclophilin, is around 15,000-20,000 daltons. Using Lineweaver-Burk analysis of binding equilibrium data, the dissociation constant of CsA for this binding site was approximately 2.2 microM. these studies, which demonstrate that CsA (i) is rapidly accumulated inside the cells as free drug but is also specifically bound to an intracellular macromolecule, and (ii) is selectively retained in the intracellular compartment after the extracellular drug is removed, could explain the intense distribution of CsA in the organs and the slow disappearance of CsA from plasma after CsA therapy in humans.

Some of 66 patients with head and neck tumors were treated with high-dose methotrexate monochemotherapy. The use of a prospective mathematical model with pharmacokinetic surveillance proved to be reliable, practical, and useful. By this means chemotherapy could be individualized, with a resultant marked reduction in the frequency and severity of toxicity. The onset of clinical toxic manifestations was significantly correlated with a poor therapeutic response and poor prognosis. The patients were classified in to three groups according to poor, intermediate, and good pharmacokinetic parameters calculated after an intravenous identification dose of methotrexate. These group allocations had a very high prognostic value with regard to toxicity, and especially to the quality of therapeutic response to high-dose methotrexate. They are suggested as useful guidelines in the prescription of high-dose methotrexate chemotherapy.

Methotrexate (MTX) and vindesine (VDS) have both been found effective in the treatment of acute leukemia. With regard to their pharmacological effects at the cellular level they can reportedly interact. Administration of MTX at high dose levels has been suggested as both a curative and preventive treatment of blastic meningitis. The purpose of this work was to determine whether an injection of VDS leads to any change in MTX clearance and uptake in the cerebrospinal fluid (CSF). The plasma pharmacokinetic and CSF influx of MTX and VDS were assayed after high dose systemic MTX with an intravenous bolus of VDS administered in the treatment of acute lymphoblastic leukemia. The MTX concentration was determined by enzymatic assay and VDS by radio immunoassay. No interrelation between these drugs was found. MTX levels in the CSF were sufficient for therapeutic effectiveness but were not affected by intravenous VDS. Detectable amounts of VDS were observed in the CSF but were not altered by MTX.

It has been suggested that the intra-erythrocyte levels of methotrexate (MTX) and its polyglutamized derivatives could offer a method for evaluating intracellular MTX accumulation and its metabolism in children with acute lymphoblastic leukemia. We were interested in measuring the intra-erythrocyte levels of MTX in patients with solid tumors receiving high-dose MTX treatment. After a first incorporation stage occurring during infusion, MTX concentrations subsequently increased 9-12 days after the treatment as polyglutamized derivatives. Thirty days after the infusion, MTX and its polyglutamates were still measurable in erythrocytes. The percentage of polyglutamization varied on an individual basis, but two groups of patients could be separated according to their ability to form polyglutamates. We also noted the presence of 7-hydroxy-methotrexate (7-OH-MTX) appearing 48 hours after the beginning of the infusion which was still present in 17/20 samples 30 days after the treatment.

Population pharmacokinetics of methotrexate (MTX) was evaluated from intravenous test-dose (TD) data (n = 20 corresponding to 174 measured samples). Bayesian prediction of MTX clearance from TD experiments combining population data with measured levels (at times 0.5 and 6 h) was found to be feasible in routine situations with good performance (root mean squared error : rmse (precision) = 1.14 1.h-1 (11.2%) and mean error : me (bias) = 0.06 1.h-1 (NS) relatively to weighted least-square estimates, n = 50). The precision of Bayesian prediction was comparable to that of the model independent which is used in routine practice and involves 9 measured levels over 30 h, (rmse = 1.35 1.h-1 (10.9%), n = 50). However, the routine method presented a significative bias (me = -0.81 1.h-1, n = 50).

Seric values have been evaluated in 24 patients receiving high doses of etoposide. In 6 patients, CNS value was evaluated simultaneously. After 2 perfusions with 250 mg/m2 at 12 h interval, seric value is 35.3 micrograms/ml + 10.3, the value after 6 perfusions is 31.1 micrograms/ml + 6.5. The variation of CNS value observed from 0.08 to 0.49 micrograms/ml is 0.36 to 1.29% of the seric value; there is no positive correlation with seric value. Only one patient out of 6 has a partial response of CNS metastases.

The pharmacokinetics of methotrexate and 7-hydroxy-methotrexate were studied in patients undergoing very high-dose methotrexate monotherapy. The patients received, first, two methotrexate intravenous bolus test doses (50 mg/m2) one with and one without concomitant administration of folinic acid (15 mg every 6 h) in a random sequence, and, second, an 8 h infusion, individualized to achieve a peak plasma concentration of 5 X 10(-4) M methotrexate (infusion rates greater than 1000 mg/h). Methotrexate and 7-hydroxy-methotrexate concentrations were measured by specific radioimmunoassays and the data were analysed simultaneously by an integrated pharmacokinetic model. Following test dose administration, methotrexate and 7-hydroxy-methotrexate plasma concentration kinetics were best described by assuming that methotrexate elimination (and 7-hydroxy-methotrexate formation) occurred from a peripheral compartment reaching rapid equilibrium with the plasma. Folinic acid administration did not influence the disposition of either compound. Following the infusion, a significant (P less than 0.01) decrease of methotrexate total plasmatic clearance occurred without modification of 7-hydroxy-methotrexate formation and elimination.

Determination of methotrexate (MTX) kinetics after an IV bolus (50 mg/m2) allows prediction of the steady-state plasma level of this drug during a constant infusion. This prediction allows high-dose MTX (HD-MTX) therapy without major toxicity. Patients with head and neck carcinoma received HD-MTX and vindesine (VDS) infusions concomitantly. The therapeutic survey of these patients showed that the predicted plasma level of MTX was not achieved in the presence of VDS. Moreover, the computed dose of MTX had to be increased by a larger amount if the MTX plasma clearance after the identification IV push was low (less than 9 l/h). In the presence of VDS, the creatinine clearance is lower than when MTX is infused alone, and MTX renal elimination is identical (MTX or MTX + VDS infusions). Thus it seems that the decrease of the MTX plasma level during MTX-VDS infusion could be due to an increase of cellular incorporation.

High-dose methotrexate (HD-MTX) infusions associated with vindesine (VDS) have been used in the treatment of head and neck cancer. In a previous study, VDS was shown to increase the apparent plasma clearance of MTX. We have studied the MTX hydroxylation process in the presence of VDS. Different routes of administration have been tested (IV pushes and 24-h or 36-h infusions). A radioimmunoassay has been developed to measure 7-OH-MTX. The defined protocols enabled us to show that VDS influences not only the pharmacokinetic behavior of methotrexate but also its hydroxylation, which is decreased in presence of VDS.

A preliminary methotrexate (MTX) kinetic evaluation following administration of an IV bolus (test-dose) allowed individualization of high-dose infusions (HD-MTX). This approach combined with therapeutic drug monitoring was found to have good performance over a large scale of predicted steady-state levels (Css) (10(-5) to 10(-4) M over 24 to 36 h) corresponding to 17 to 650 mg/h deliveries (root mean squared error : rmse (precision) = 1.54 X 10(-5) M (21.4%) and mean error : me (bias) = 0.043 X 10(-5) M (NS)). However a significative (p less than 0.05) but rather low over-estimation of dosage (me = 7.38 X 10(-5) M (14.8%)) associated to a decrease in the prediction precision (rmse = 13.3 X 10(-5) M (26.6%)) occurred in 5 X 10(-4) M predicted Css over 8 h (970 to 1970 mg/h deliveries). However in a number of cases (6 out of 29) important deviations from predicted Css occurred, implying the need to stop the infusion before 8 h. These results indicated that MTX pharmacokinetics was linear from low test-dose bolus injections to high-dose infusions. This allowed dosage predictions based upon preliminary estimation of MTX clearance and associated to therapeutic drug monitoring during and following infusion.