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Background: There are few data on the treatment of children and adolescents with multidrug-resistant (MDR) or rifampicin-resistant (RR) tuberculosis, especially with more recently available drugs and regimens. We aimed to describe the clinical and treatment characteristics and their associations with treatment outcomes in this susceptible population., Methods: We conducted a systematic review and individual participant data meta-analysis. Databases were searched from Oct 1, 2014, to March 30, 2020. To be eligible, studies must have included more than five children or adolescents (0-19 years of age) treated for microbiologically confirmed or clinically diagnosed MDR or RR tuberculosis within a defined treatment cohort, and reported on regimen composition and treatment outcomes. Abstracts were screened independently by two authors to identify potentially eligible records. Full texts were reviewed by two authors independently to identify studies meeting the eligiblity criteria. For studies meeting eligiblity criteria, anonymised individual patient data was requested and individiual level data included for analysis. The main outcome assessed was treatment outcome defined as treatment success (cure or treatment completed) versus unfavourable outcome (treatment failure or death). Multivariable logistic regression models were used to identify associations between clinical and treatment factors and treatment outcomes. This study is registered with Prospero (CRD42020187230)., Findings: 1417 studies were identified through database searching. After removing duplicates and screening for eligibility, the search identified 23 369 individual participants from 42 studies, mostly from India and South Africa. Overall, 16 825 (72·0%) were successfully treated (treatment completed or cured), 2848 died (12·2%), 722 (3·1%) had treatment failure, and 2974 (12·7%) were lost to follow-up. In primary analyses, the median age was 16 (IQR 13-18) years. Of the 17 764 (87·1%) participants with reported HIV status, 2448 (13·8%) were living with HIV. 17 707 (89·6%) had microbiologically confirmed tuberculosis. After adjusting for significant factors associated with treatment outcome, the use of two (adjusted odds ratio [OR] 1·41 [95% CI 1·09-1·82]; p=0·008) or three (2·12 [1·61-2·79]; p<0·0001) WHO-classified group A drugs (bedaquiline, moxifloxacin, levofloxacin, and linezolid) compared with the use of no group A drugs at all was positively associated with treatment success., Interpretation: Younger and clinically diagnosed children are underrepresented among those treated for MDR and RR tuberculosis and should be a focus for case-finding efforts. Overall treatment outcomes in our analysis were better than in adults but lower than the international targets of 90% or more individuals successfully treated. Treatment with more group A drugs was associated with better treatment outcomes in children and adolescents, highlighting the need for more rapid access to these drugs and improved regimens., Funding: Unitaid., Competing Interests: Declaration of interests AJG-P reports that his institution receives grant funding from the US National Institutes of Health (NIH) and Unitaid for paediatric studies of bedaquiline, delamanid, pretomanid, clofazimine, moxifloxacin, and levofloxacin. J-JY reports donations of linezolid (Zyvox) from Pfizer, Delamanid (Deltyba) from Otsuka Pharmaceutical, and Rifampicin (Rifampcin) from Yuhan for the for the clinical trials, in which he served as a principal investigator. JF reports grant funding form the Stop TB Partnership's Global Drug Facility. JRC reports grant funding to his institution from the Canadian Institutes of Health, Fonds de recherche du Quebec-Sante, the National Sanatorium Association, and WHO; and consulting fees from WHO, the World Bank, and the Saskatchewan Auditors Office. BSG reports grant funding from the Carlos III Institute of Health, Ministry of Economy and Competitiveness (Spain). GEV reports grant funding from the NIH, US Agency for International Development (USAID), Unitaid, Medecins Sans Frontiers, and Partners in Health; and consulting fees from the Gates Medical Research Institute. RS reports grant funding from the NIH, the Bill and Melinda Gates Foundation, USAID, and from UNITE4TB (Academia and Industry United Innovation and Treatment for Tuberculosis). AS reports participating at the Research Lead at UK Academics and Professionals to end Tuberculosis. All other authors declare no competing interests., (Copyright © 2025 World Health Organization. Published by Elsevier Ltd. 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Purpose: Little is known regarding differences in childhood growth between somatic and heritable retinoblastoma (Rb) populations. We aimed to compare childhood growth parameters between somatic and heritable Rb cohorts at birth and at time of diagnosis with Rb., Methods: A multinational, longitudinal cohort study was conducted with patients from 11 centers in 10 countries who presented with treatment naïve Rb from January to December 2019. Variables of interest included age, sex, and size characteristics at birth and at time of presentation, as well as germline mutation status. After Bonferroni correction, results were statistically significant if the P value was less than 0.005., Results: We enrolled 696 patients, with 253 analyzed after exclusion criteria applied. Between somatic (n = 39) and heritable (n = 214) Rb cohorts, with males and females analyzed separately, there was no significant difference in birth weight percentile, weight percentile at time of diagnosis, length percentile at time of diagnosis, weight-for-length percentile at time of diagnosis, or change of weight percentile from birth to time of diagnosis. Patients with heritable Rb had a smaller mean weight percentile at birth and smaller mean weight and length percentiles at time of diagnosis with Rb, although this difference was not statistically significant. All cohorts experienced a slight negative change of weight percentile from birth to time of diagnosis. No cohort mean percentiles met criteria for failure to thrive, defined as less than the 5th percentile., Conclusions: Children with Rb seem to have normal birth and childhood growth patterns. There is no definitive evidence that somatic or heritable Rb has a biological or environmental impact on childhood growth parameters.

Background: Invasive dental treatment in patients exposed to antiresorptive and antiangiogenic drugs can cause medication-related osteonecrosis of the jaw (MRONJ). Currently, the exact pathogenesis of this disease is unclear., Methods: In March 2022, Medline (Ovid), Embase (Ovid), Scopus, and Web of Science were screened to identify eligible in vitro studies investigating the effects of antiresorptive and antiangiogenic compounds on orally derived cells., Results: Fifty-nine articles met the inclusion criteria. Bisphosphonates were used in 57 studies, denosumab in two, and sunitinib and bevacizumab in one. Zoledronate was the most commonly used nitrogen-containing bisphosphonate. The only non-nitrogen-containing bisphosphonate studied was clodronate. The most frequently tested tissues were gingival fibroblasts, oral keratinocytes, and alveolar osteoblasts. These drugs caused a decrease in cell proliferation, viability, and migration., Conclusions: Antiresorptive and antiangiogenic drugs displayed cytotoxic effects in a dose and time-dependent manner. Additional research is required to further elucidate the pathways of MRONJ.

Objective: To test whether systemic cytokine release is associated with central nervous system inflammatory responses and glial injury in immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor (CAR)-T cell therapy in children and young adults., Methods: We performed a prospective cohort study of clinical manifestations as well as imaging, pathology, CSF, and blood biomarkers on 43 subjects ages 1 to 25 who received CD19-directed CAR/T cells for acute lymphoblastic leukemia (ALL)., Results: Neurotoxicity occurred in 19 of 43 (44%) subjects. Nine subjects (21%) had CTCAE grade 3 or 4 neurological symptoms, with no neurotoxicity-related deaths. Reversible delirium, headache, decreased level of consciousness, tremor, and seizures were most commonly observed. Cornell Assessment of Pediatric Delirium (CAPD) scores ≥9 had 94% sensitivity and 33% specificity for grade ≥3 neurotoxicity, and 91% sensitivity and 72% specificity for grade ≥2 neurotoxicity. Neurotoxicity correlated with severity of cytokine release syndrome, abnormal past brain magnetic resonance imaging (MRI), and higher peak CAR-T cell numbers in blood, but not cerebrospinal fluid (CSF). CSF levels of S100 calcium-binding protein B and glial fibrillary acidic protein increased during neurotoxicity, indicating astrocyte injury. There were concomitant increases in CSF white blood cells, protein, interferon-γ (IFNγ), interleukin (IL)-6, IL-10, and granzyme B (GzB), with concurrent elevation of serum IFNγ IL-10, GzB, granulocyte macrophage colony-stimulating factor, macrophage inflammatory protein 1 alpha, and tumor necrosis factor alpha, but not IL-6. We did not find direct evidence of endothelial activation., Interpretation: Our data are most consistent with ICANS as a syndrome of systemic inflammation, which affects the brain through compromise of the neurovascular unit and astrocyte injury. ANN NEUROL 2019., (© 2019 American Neurological Association.)

Extensively drug-resistant tuberculosis (XDR TB) has extremely poor treatment outcomes in adults. Limited data are available for children. We report on clinical manifestations, treatment, and outcomes for 37 children (<15 years of age) with bacteriologically confirmed XDR TB in 11 countries. These patients were managed during 1999-2013. For the 37 children, median age was 11 years, 32 (87%) had pulmonary TB, and 29 had a recorded HIV status; 7 (24%) were infected with HIV. Median treatment duration was 7.0 months for the intensive phase and 12.2 months for the continuation phase. Thirty (81%) children had favorable treatment outcomes. Four (11%) died, 1 (3%) failed treatment, and 2 (5%) did not complete treatment. We found a high proportion of favorable treatment outcomes among children, with mortality rates markedly lower than for adults. Regimens and duration of treatment varied considerably. Evaluation of new regimens in children is required.

Purpose To compare the diagnostic accuracy of gallium 68 ( 68 Ga)-labeled prostate-specific membrane antigen (PSMA)-11 PET/MRI with that of multiparametric MRI in the detection of prostate cancer. Materials and Methods The authors performed a retrospective study of men with biopsy-proven prostate cancer who underwent simultaneous 68 Ga-PSMA-11 PET/MRI before radical prostatectomy between December 2015 and June 2017. The reference standard was whole-mount pathologic examination. Readers were blinded to radiologic and pathologic findings. Tumor localization was based on 30 anatomic regions. Region-specific sensitivity and specificity were calculated for PET/MRI and multiparametric MRI by using raw stringent and alternative neighboring approaches. Maximum standardized uptake value (SUV max ) in the tumor and Prostate Imaging Reporting and Data System (PI-RADS) version 2 grade were compared with tumor Gleason score. Generalized estimating equations were used to estimate population-averaged sensitivity and specificity and to determine the association between tumor characteristics and SUV max or PI-RADS score. Results Thirty-two men (median age, 68 years; interquartile range: 62-71 years) were imaged. The region-specific sensitivities of PET/MRI and multiparametric MRI were 74% (95% confidence interval [CI]: 70%, 77%) and 50% (95% CI: 45%, 0.54%), respectively, with the alternative neighboring approach (P < .001 for both) and 73% (95% CI: 68%, 79%) and 69% (95% CI: 62%, 75%), respectively, with the population-averaged generalized estimating equation (P = .04). Region-specific specificity of PET/MRI was similar to that of multiparametric MRI with the alternative neighboring approach (88% [95% CI: 85%, 91%] vs 90% [95% CI: 87%, 92%], P = .99) and in population-averaged estimates (70% [95% CI: 64%, 76%] vs 70% [95% CI: 64%, 75%], P = .99). SUV max was associated with a Gleason score of 7 and higher (odds ratio: 1.71 [95% CI: 1.27, 2.31], P < .001). Conclusion The sensitivity of gallium 68-labeled prostate-specific membrane antigen-11 PET/MRI in the detection of prostate cancer is better than that of multiparametric MRI. © RSNA, 2018 See also the editorial by Civelek in this issue.

Background: An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children., Methods and Findings: To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data (IPD) meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field, and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of three children (aged <15 years) who were treated for bacteriologically confirmed or clinically diagnosed MDR-TB, and if treatment outcomes were reported. The search yielded 2,772 reports; after review, 33 studies were eligible for inclusion, with IPD provided for 28 of these. All data were from published or unpublished observational cohorts. We analyzed demographic, clinical, and treatment factors as predictors of treatment outcome. In order to obtain adjusted estimates, we used a random-effects multivariable logistic regression (random intercept and random slope, unless specified otherwise) adjusted for the following covariates: age, sex, HIV infection, malnutrition, severe extrapulmonary disease, or the presence of severe disease on chest radiograph. We analyzed data from 975 children from 18 countries; 731 (75%) had bacteriologically confirmed and 244 (25%) had clinically diagnosed MDR-TB. The median age was 7.1 years. Of 910 (93%) children with documented HIV status, 359 (39%) were infected with HIV. When compared to clinically diagnosed patients, children with confirmed MDR-TB were more likely to be older, to be infected with HIV, to be malnourished, and to have severe tuberculosis (TB) on chest radiograph (p < 0.001 for all characteristics). Overall, 764 of 975 (78%) had a successful treatment outcome at the conclusion of therapy: 548/731 (75%) of confirmed and 216/244 (89%) of clinically diagnosed children (absolute difference 14%, 95% confidence interval [CI] 8%-19%, p < 0.001). Treatment was successful in only 56% of children with bacteriologically confirmed TB who were infected with HIV who did not receive any antiretroviral treatment (ART) during MDR-TB therapy, compared to 82% in children infected with HIV who received ART during MDR-TB therapy (absolute difference 26%, 95% CI 5%-48%, p = 0.006). In children with confirmed MDR-TB, the use of second-line injectable agents and high-dose isoniazid (15-20 mg/kg/day) were associated with treatment success (adjusted odds ratio [aOR] 2.9, 95% CI 1.0-8.3, p = 0.041 and aOR 5.9, 95% CI 1.7-20.5, p = 0.007, respectively). These findings for high-dose isoniazid may have been affected by site effect, as the majority of patients came from Cape Town. Limitations of this study include the difficulty of estimating the treatment effects of individual drugs within multidrug regimens, only observational cohort studies were available for inclusion, and treatment decisions were based on the clinician's perception of illness, with resulting potential for bias., Conclusions: This study suggests that children respond favorably to MDR-TB treatment. The low success rate in children infected with HIV who did not receive ART during their MDR-TB treatment highlights the need for ART in these children. Our findings of individual drug effects on treatment outcome should be further evaluated., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: DF, MG, and MvDB are staff members of the World Health Organization (WHO). AJGP's institution, Stellenbosch University, has received funds from the US National Institutes of Health for an observational study of the pharmacokinetics and safety of key second-line TB medications in children, for which AJGP is the Principal Investigator. AJGP's institution has also received funds from Otsuka Pharmaceuticals for implementation of pediatric trial of the novel TB drug delamanid; AJGP is the PI for his site for this trial.

Purpose: To evaluate acquisition time and clinical image quality of a variable refocusing flip angle (vrf) single-shot fast spin echo (SSFSE) sequence in comparison with a conventional SSFSE sequence for imaging of liver lesions in patients undergoing whole-body PET/MRI for oncologic staging., Methods: A vrfSSFSE sequence was acquired in 43 patients with known pancreatic neuroendocrine tumors undergoing 68 Ga-DOTA-TOC PET on a simultaneous time-of-flight 3.0T PET/MRI. Liver lesions ≥1.5 cm with radionucleotide uptake were analyzed. Contrast-to-noise ratios (CNRs) were measured, and four blinded radiologists assessed overall image quality. Differences in repetition time and CNR were assessed using a paired Student's t test with p < 0.05 considered statistically significant. Inter-reader variability was assessed with Fleiss' kappa statistic., Results: 53 eligible lesions in 27 patients were included for analysis. vrfSSFSE demonstrated higher mean lesion CNR compared to SSFSE (9.9 ± 4.1 vs. 6.7 ± 4.1, p < 0.001). Mean repetition time (TR) was 679 ± 97 ms for the vrfSSFSE sequence compared to 1139 ± 106 ms for SSFSE (p < 0.0001), corresponding to a 1.7-fold decrease in acquisition time. Overall quality of liver lesion and common bile duct images with the vrfSSFSE sequence was graded as superior than or equivalent to the SSFSE sequence for 59% and 67% of patients, respectively., Conclusions: Compared to conventional SSFSE, vrfSSFSE resulted in improved lesion contrast on simultaneous PET/MRI in patients with liver metastases. Due to decreased SAR demands, vrfSSFSE significantly decreased TR, allowing coverage of the entire liver in a single twenty-second breath hold. This may have important clinical implications in the setting of PET/MRI, where scan time is limited by the necessity of whole-body image acquisition in addition to bed specific imaging.

In a long-term (10-year) study of radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) as bridging therapy in patients listed for orthotopic liver transplantation (LT), we evaluated the impact of RFA on waiting list dropout rate, post-LT tumor recurrence, and long-term intention-to-treat, disease-specific survival (DSS). From March 2004 to October 2014, RFA was performed as the initial stand-alone bridge therapy to LT for 121 patients (men/women ratio, 83:38; mean age, 60.0 years) with 156 de novo HCCs (mean size, 2.4 cm). Follow-up period from initial RFA ranged from 1.3 to 128.0 months (median, 42.9 months). We assessed the overall and tumor-specific waiting list dropout rates, post-LT tumor recurrence, and 10-year post-LT and intention-to-treat survival rates. Dropout from the waiting list due to tumor progression occurred in 7.4% of patients. HCC recurrence after LT occurred in 5.6% of patients. The post-LT overall survival (OS) rate at 5 and 10 years was 75.8% and 42.2%, respectively, and the recurrence-free survival (RFS) rate was 71.1% and 39.6%, respectively. Intention-to-treat OS, RFS, and DSS rates for the entire study population at 5 and 10 years were 63.5% and 41.2%, 60.8% and 37.7%, and 89.5% and 89.5%, respectively., Conclusion: RFA as a first-line stand-alone bridge therapy to LT achieves excellent long-term overall and tumor-specific survivals, with a low dropout rate from tumor progression despite long wait list times and a sustained low tumor recurrence rate upon post-LT follow-up of up to 10 years. (Hepatology 2017;65:1979-1990)., (© 2017 by the American Association for the Study of Liver Diseases.)

Purpose: To evaluate the performance of diffusion-weighted imaging (DWI) and T2-weighted single shot fast spin-echo (SSFSE) imaging of the liver in the detection of hepatocellular carcinoma (HCC) in reference to the LI-RADS classification system., Methods: MR images of 40 patients with 68 LI-RADS grade 3-5 lesions were analyzed. Two readers independently reviewed sequences and characterized lesion signal intensity, followed by consensus evaluation. CE-MRI served as reference standard. Sensitivities were compared across sequences. Lesion-to-liver contrast-to-noise ratios (CNRs) and apparent diffusion coefficients (ADCs) were measured and compared using the Wilcoxon signed-rank test across sequences and the Mann-Whitney U or Kruskal-Wallis test between LI-RADS categories. Inter-reader variability was assessed using Cohen's kappa statistic., Results: Consensus sensitivities of LI-RADS 3-5 lesions using SSFSE images versus DWI were similar (0.53-0.63, p=0.089), however, the sensitivity with DWI b=700 was higher (0.63) than DWI b=0 (0.53, p=0.039). Lesion-to-liver CNRs were larger for all DWI sequences compared to SSFSE images (p<0.001 for all). ADCs of large (>2cm) LIRADS 3-5 lesions were lower than those of small lesions (1.09±0.33 vs. 1.31±0.26, p=0.02), however lesion ADCs were not different from those of adjacent hepatic parenchyma for any LI-RADS lesion., Conclusions: DWI has a similar sensitivity compared to SSFSE, but intensity on DWI likely represents intrinsic T2 signal hyper-intensity rather than restricted diffusion as the ADC values were not lower than adjacent parenchyma. Therefore it may not be appropriate to consider hyper-intensity on high b-value as a separate ancillary criteria to T2 hyper-intensity in LI-RADS., (Published by Elsevier Inc.)

Purpose: To evaluate preliminary outcomes after microwave ablation (MWA) of hepatocellular carcinoma (HCC) up to 5 cm and to determine the influence of tumor size., Materials and Methods: Electronic records were searched for HCC and MWA. Between January 2011 and September 2014, 173 HCCs up to 5 cm were treated by MWA in 129 consecutive patients (89 men, 40 women; mean age, 66.9 y ± 9.5). Tumor characteristics related to local tumor progression and primary and secondary treatment efficacy were evaluated by univariate analysis. Outcomes were compared between tumors ≤ 3 cm and tumors > 3 cm., Results: Technical success, primary efficacy, and secondary efficacy were 96.5%, 99.4%, and 94.2% at a mean follow-up period of 11.8 months ± 9.8 (range, 0.8-40.6 mo). Analysis of tumor characteristics showed no significant risk factor for local tumor progression, including subcapsular location (P = .176), tumor size (P = .402), and perivascular tumor location (P = .323). The 1-year and 2-year secondary or overall treatment efficacy rates for tumors measuring ≤ 3 cm were 91.2% and 82.1% and for tumors 3.1-5 cm were 92.3% and 83.9% (P = .773). The number of sessions to achieve secondary efficacy was higher in the larger tumor group (1.13 vs 1.06, P = .005). There were three major complications in 134 procedures (2.2%)., Conclusions: With use of current-generation MWA devices, percutaneous ablation of HCCs up to 5 cm can be achieved with high efficacy., (Copyright © 2016 SIR. Published by Elsevier Inc. All rights reserved.)

Triatoma dimidiata (Latreille, 1811) is the most abundant and significant insect vector of the parasite Trypanosoma cruzi in Central America, and particularly in Guatemala. Tr. cruzi is the causative agent of Chagas disease, and successful disease control requires understanding the geographic distribution and degree of migration of vectors such as T. dimidiata that frequently re-infest houses within months following insecticide application. The population genetic structure of T. dimidiata collected from six villages in southern Guatemala was studied to gain insight into the migration patterns of the insects in this region where populations are largely domestic. This study provided insight into the likelihood of eliminating T. dimidiata by pesticide application as has been observed in some areas for other domestic triatomines such as Triatoma infestans. Genotypes of microsatellite loci for 178 insects from six villages were found to represent five genetic clusters using a Bayesian Markov Chain Monte Carlo method. Individual clusters were found in multiple villages, with multiple clusters in the same house. Although migration occurred, there was statistically significant genetic differentiation among villages (FR T = 0.05) and high genetic differentiation among houses within villages (FSR = 0.11). Relatedness of insects within houses varied from 0 to 0.25, i.e., from unrelated to half-sibs. The results suggest that T. dimidiata in southern Guatemala moves between houses and villages often enough that recolonization is likely, implying the use of insecticides alone is not sufficient for effective control of Chagas disease in this region and more sustainable solutions are required., (© The Authors 2015. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Setting: Pediatric multidrug-resistant tuberculosis (MDR-TB) is complicated by difficult diagnosis, complex treatment, and high mortality. In South Africa, these challenges are amplified by human immunodeficiency virus (HIV) co-infection; however, evidence on treatment outcomes among co-infected children is limited., Objective: Using conventional and new pediatric definitions, to describe treatment outcomes and identify risk factors for unfavorable outcome and mortality in children aged <15 years with MDR-TB or extensively drug-resistant TB (XDR-TB) in KwaZulu-Natal, South Africa., Design: Retrospective cohort study in a regional TB referral hospital., Results: From January 2009 to June 2010, 84 children (median age 8 years, IQR 4-12) with MDR-TB (n = 78) or XDR-TB (n = 6) initiated treatment. Sixty-four (77%) were HIV-positive and 62 (97%) received antiretroviral therapy. Sixty-six (79%) achieved favorable treatment outcomes. Overall mortality was 11% (n = 9) at 18 months after initiation of treatment. Malnutrition (aOR 27.4, 95%CI 2.7-278.7) and severe radiographic findings (aOR 4.68, 95%CI 1.01-21.9) were associated with unfavorable outcome. New pediatric outcome definitions increased the proportion classified as cured., Conclusion: It is possible to successfully treat pediatric MDR-TB-HIV even in resource-poor settings. Malnutrition is a marker for severe TB-HIV disease, and is a potential target for future interventions in these patients.

Objectives: The efficacy of a concomitant oxaliplatin/bolus 5-fluorouracil/leucovorin regimen in 123 heavily pretreated patients with advanced colorectal cancer was evaluated. Patients with an Eastern Cooperative Oncology Group performance status of 0 to 2 and radiographically progressive cancer which failed to respond to between two and five prior treatment modalities were consented and enrolled., Methods: Patients received oxaliplatin on day 1 of weeks 1, 3, and 5 of an 8-week cycle. 5-fluorouracil/leucovorin was administered on day 1 of weeks 1 through 6., Results: Grade 3 to 4 toxicities were as follows: diarrhea 30%; vomiting 11%; hematologic < 3%; peripheral neuropathy 2.5%. Of the 101 patients evaluable for response, 7% achieved a partial response (median duration 4.25 mo), 1 patient achieved a minor response (7 mo), and 31% had stable disease (median duration 6.08 mo). The median time to progression was 3.6 months., Conclusion: This regimen in heavily pretreated patients with disseminated colorectal cancer is of modest benefit, often at the expense of considerable gastrointestinal toxicity. It appears that the use of oxaliplatin/bolus 5-fluorouracil/leucovorin is more toxic than oxaliplatin/infusional 5-fluorouracil and possibly less effective.

he comparative teratogenicity of nine retinoids in Wistar rats was investigated. The compounds studied and dose levels tested (mg/kg) were: all-trans-retinoic acid (TRA), 6.25, 12.5, 25, 50, 100; etretinate (ETR), 25, 50; acitretin (ACIT), 25, 50; 13-cis-retinoic acid (13CRA), 100, 200; and five retinamides, each at 300 and 600 mg/kg, N-(4-hydroxyphenyl)-retinamide (4HPR); N-tetrazol-5-ylretinamide (TZR); N-butylretinamide (NBR); N-ethylretinamide (NER); 13-cis-N-ethylretinamide (13CNER). Retinoids were administered by oral intubation on days 10 and 11 post coitum (p.c.). Dams were killed on day 22 p.c. and examinations carried out to assess teratogenic potential. TRA, ETR, ACIT, 13CRA and 4HPR increased the incidence of resorptions. The incidence of abnormal fetuses, irrespective of the specific abnormalities induced, was markedly increased (50-100%) by TRA, ETR, ACIT, 13CRA and 4HPR, whereas TZR and NBR caused moderate increases (20-50%), and NER and 13CNER induced mild increases (10-20%). The incidences of CNS, craniofacial and urinogenital defects were generally high with TRA, ETR, ACIT and 13CRA. Cardiac vessel defects were markedly increased by 4HPR. Using a number of criteria, a generalized ranking order of the toxicity of the compounds was drawn up: TRA > ETR > ACIT > 13CRA > 4HPR > TZR identical to NBR > NER identical to 13CNER. The ranked order of relative in-vivo teratogenicity for the nine retinoids is compared with a previously reported in-vitro assessment of the compounds using a rat whole embryo culture technique.

Several multivariate statistical methods are available which can alleviate the problems of analysing the large volumes of data generated from toxicological experiments. One such technique, principal components analysis, provides a method for exploring the relationships between a number of variables (such as blood parameters) and for eliminating redundant data if strong correlations exist between the characters. It also provides a method for clustering individuals, which may reveal similarities between animals in a treatment group or highlight individual 'outliers'. The application of principal components analysis to a set of haematological data from a trial evaluating the efficacy of a synthetic retinoid against carcinogen-induced bladder cancer in the rat has clearly shown, in two bivariate plots, that while some animals in the carcinogen-treated groups were normal, others were anaemic and that animals fed the synthetic retinoid and killed at 1 year had a microcytic anaemia. A full exploration of the data using conventional univariate statistical analysis would have involved at least 28 graphic representations of the data, as well as the interpretation of more than 130 means and SDs. Principal components analysis provides a valuable additional tool for the statistical analysis and exploration of toxicological data, but it must be used in conjunction with univariate or other multivariate methods if hypothesis testing is required. The use of multivariate techniques in toxicology may best be assessed by their practical application to toxicological data, and this paper presents such an evaluation with the aim of encouraging further exploration of the usefulness of principal components analysis. The raw data on which most analyses have been carried out are given.

Three nephrectomy specimens with transitional cell carcinoma (TCC) of the renal pelvis were thoroughly examined by both light and scanning electron microscopy. The tumours as well as the urothelium of the upper urinary tract were studied. In all three cases, extensive areas of the urothelium, even in places remote from the tumours, were found by scanning electron microscopy (SEM) to be covered by pleomorphic microvilli. This suggests that there is a widespread failure of differentiation of the urothelium to a much greater extent than can be appreciated by conventional light microscopy.

This study examines the effects of in-vivo immune regulation by vitamin A acetate (VAA) and 13-cis-retinoic acid (13-CRA) on in-vitro accessory cell function. Mice were fed a control diet, or diet containing VAA or 13-CRA, and monitored by body weight gains and diet consumptions at weekly intervals. At 4, 7 and 12 weeks mice were killed, differential blood counts performed and accessory cells isolated from lymphomedullary tissues. Histology confirmed that the chief feature of the lymphomedullary organs of the VAA-fed animals was an expansion of the splenic marginal zone and the paracortical region of the lymph nodes. There was an increase in the number of accessory cells present, and this included both dendritic cells and macrophages. The accessory cell function of these cells was also increased, as evidenced by both alloproliferative and allocytotoxic responses in vitro. In 13-CRA-fed animals the effects were similar to those seen with VAA, but were less pronounced. We suggest that the primary effects of these compounds on in-vivo immunoregulation could be due to their promotion of accessory cell function.

In nine patients, who underwent radical cystectomy for transitional cell carcinoma of the bladder, detailed maps were prepared of results of the light microscopic findings and of the surface features of the urothelium as observed by scanning electron microscopy. Scanning electron microscopy revealed a more widespread distribution of residual neoplastic disease than suspected by light microscopy alone. This observation is based on the presence of abnormal cells carrying pleomorphic microvilli in association with other cells infrequently seen in normal healthy urothelium. Such changes have been directly related to neoplastic transformation in numerous experimental studies and have also been observed in human transitional cell carcinoma. This widespread distribution of these markers for neoplastic transformation explains the multiple recurrences of transitional cell carcinoma which characterises neoplastic disease of the bladder.

As little comprehensive baseline data are available on age-related haematological changes in genetically-defined rat strains, the haematology of female F344 rats is described in animals sampled at 2, 4, 8, 20, 66 and 121 weeks of age. Values for Hb, RBC and PCV increased from 2 weeks of age to reach adult levels at 8 weeks, whereas MCV, MCH and reticulocyte counts were high initially but decreased to reach the adult range at 8 weeks. Between 66 and 121 weeks, reticulocyte counts were significantly increased and values for MCHC significantly decreased. Lymphocytes were the predominant white cell type in each age group. The absolute numbers of neutrophils and lymphocytes showed slight variations between 2 and 66 weeks and both cell types increased significantly between 66 and 121 weeks. Platelet counts showed no overall age-related trends. Fibrinogen values increased from 2 weeks of age to reach the adult level at 8 weeks. One animal of the 14 sampled at 121 weeks showed changes in the blood, liver and spleen consistent with a diagnosis of lymphoid leukaemia.

In Egypt, bladder cancer incidence is high in areas where the prevalence and intensity of Schistosoma haematobium infection is also high. Experimental evidence shows bladder carcinogenesis to be a multi-stage process which can be accelerated by many factors. N-nitroso compounds, some of which are known bladder carcinogens, can be formed from amine precursors and nitrate in urine during some bacterial infections. In experimental animals the growth of nitrosamine-induced urothelial cancers is accelerated by damage to the urothelium caused by S. haematobium infections, and by analogy in man this could account for the lower peak age of incidence of this cancer in Egypt by comparison with Europe. The present study was designed to investigate whether bacterial infection of the urinary tract was common in areas of endemic schistosomiasis and whether N-nitrosamines were regularly found to be associated with bacteriuria. Urine samples from young men in the Qalyub area of Egypt and from an adjacent Delta region were analysed for S. haematobium ova, the nature and intensity of any bacterial infection, nitrate and nitrite, and total N-nitroso compounds plus volatile N-nitrosamines. A relatively high prevalence of bacteriuria was found in young men with schistosomiasis and low levels of N-nitroso compounds were present in all specimens. When the groups were sub-divided on the basis of the ability of their bacterial flora to reduce nitrate to nitrite (the latter is required for the nitrosation of amine precursors to N-nitroso compounds), significantly higher levels of N-nitroso compounds were found in S. haematobium-infected individuals also infected with nitrate-reducing bacteria by comparison either with uninfected controls (p less than 0.0005) or with those infected with non-nitrate-reducing bacteria (p less than 0.001). The results show N-nitroso compounds to be present in the urines of young men in areas of endemic S. haematobium infection in Egypt, and elevated levels of urinary N-nitroso compounds to be associated with infection of the urinary tract by various species of nitrate-reducing bacteria.

Experiments were conducted to determine the dose response of rat bladder urothelium to a range of different single and fractionated intravesicular doses of the carcinogen, N-methyl-N-nitrosourea (MNU). A dose-related response of bladder-tumour incidence to single graded doses of MNU was found, and a threshold does suitable for use of multistage carcinogenesis experiments was derived from these data. For any given total dose of MNU, the tumour incidence was greater if the MNU had been administered in several small fractions than if it had been administered in fewer larger ones. Extending the interval between doses did not reduce the tumour incidence. It is argued that these results support the multistage theory of carcinogenesis. The histopathology and cell-surface alterations which characterize the development of MNU-induced bladder cancer are described and the contribution of hyperplasia and calculi are discussed.

The use of cystoscopy is advocated as an aid to the early differential diagnosis of disease of the canine bladder. Techniques are described for carrying out urethroscopy and cystoscopy in both male and female dogs using modern medical diagnostic instruments. Males were examined with flexible paediatric bronchofibrescopes, which permitted urethroscopy and cystoscopy, but to obtain extensive biopsies or undertake cauterisation of the bladder surface with rigid endoscopes, a simple perineal urethrostomy was necessary. The bladder of females, on the other hand, was examined by cystoscopy and biopsied using standard rigid cystoscopes and resectoscopes.

The effects of x-irradiation on the subcellular structure of the human urinary bladder were investigated by electron microscopic examination of biopsies taken during check cystoscopies from 25 patients between 1 month and 22 years after completion of a course of therapeutic radiation. All tissues of the bladder wall were damaged to some extent by the treatment. In the urothelium this was reflected by the development of more than the usual numbers of lysosomes and autophagic vacuoles in all cell layers. In the bladder wall, large often binucleate or multinucleate fibroblasts were prominent and persistent in all specimens and were associated with the development of progressive fibrosis. The vasculature and the muscle coats of the bladder wall were also damaged. In the blood vessels many endothelial cells were oedematous or necrotic and some intravascular coagulation was also observed. Smooth muscle cells became oedematous soon after irradiation, and after longer time intervals there was focal death and loss of individual muscle cells. The observed degeneration and extensive necrosis of the bladder wall, which involved severe destruction and disorganization of the muscular layers, is sufficient to explain the clinical sequelae of bladder irradiation, namely loss of elasticity, reduced capacity and incomplete micturition with residual urine.

Transforming growth factors alpha and beta (TGF-alpha and TGF-beta) isolated from normal mouse kidney induced gross morphological changes in rat urothelial cells maintained in organ culture. These morphological effects are similar to those observed after long-term treatment of rat bladder organ cultures with the carcinogen N-methyl-N-nitrosourea (MNU) or the promoting agents sodium saccharin and sodium cyclamate. Cultures were treated continuously with 5-25 micrograms/ml of Bio-Gel P-30-purified TGF containing both TGF-alpha and TGF-beta between days 1 and 14 in culture, or with 5 micrograms/ml from days 28 to 42. Controls received 1-10 ng/ml epidermal growth factor (EGF) or control medium. Untreated controls retained a normal urothelium throughout the period of study. Mature superficial-type cells covered most of the surface and less mature forms appeared on the cut sides and damaged areas where cells followed the normal pattern of urothelial differentiation. EGF at 5 and 10 ng/ml caused necrosis of the entire urothelium but at 1 and 2 ng/ml had minimal effects on histology and scanning electron microscopical appearance up to 14 days in culture. Crude P-30-purified TGFs induced a series of dose-related changes from 4 days, which were maximal at 8 days and persisted or decreased between 8 and 14 days. These included hyperplasia, loss of epithelial polarity, hyperchromasia and elongation of basal cells between the overlying cell layers to reach the culture surface. Scanning electron microscopy showed the appearance at the culture surface of immature cells with gross surface abnormalities including large numbers of blebs, stubby microvilli and long pleomorphic microvilli. Immature cells on the sides of the culture and in damaged areas developed similar features. At crude TGF doses of 10 micrograms/ml many superficial cells were rounded, some became cystic and epithelial necrosis was observed. Cultures treated with h.p.l.c.-purified TGF-beta at 80 ng/ml in the presence of 2 ng/ml EGF showed similar effects to those treated with 5 micrograms/ml P-30-purified TGF. Fully differentiated cultures treated from 28 to 42 days with crude TGF, showed changes similar to those seen in early cultures. However, histological changes, particularly basal cell elongation were more widespread and there was an abnormal development of globular processes between the membrane ridges of mature superficial cells. Neither crude TGF nor EGF stimulated growth in soft agar of isolated epithelial cells from freshly killed rats or organ cultures pretreated for 7 days with EGF or TGF.(ABSTRACT TRUNCATED AT 400 WORDS)

Single toxic doses of 1,2-dimethylhydrazine induced mild centrilobular necrosis of the liver in rats and mice. Ultrastructural studies showed hepatic nuclear changes including nucleolar microsegregation and changes in the endoplasmic reticulum and mitochondria. 1-Methylhydrazine caused little morphological change in the liver. Tumours of the colon and kidney and also massive cystic hyperplasia of the liver were found in some of the rats and tumours of the anal margin and kidney in some of the mice, following single doses of 1,2-dimethylhydrazine. Incorporation of amino acids into rat liver proteins was inhibited by 1,2-dimethylhydrazine, which also caused disaggregation of hepatic polysomes. No effects on hepatic protein synthesis by 1,1-dimethylhydrazine or 1-methylhydrazine were observed. Similarities between the effects of 1,2-dimethylhydrazine, cycasin and dimethylnitrosamine are discussed.

The luminal plasma membrane of calf urinary bladder epithelium (urothelium) has been isolated by a method designed to preserve enzymic activity as well as structural integrity. The yield was about 80 micrograms per calf bladder. Low levels of 5' nucleotidase, Mg2+-ATPase and (Na+ + K+)-ATPase activities were found in the luminal membrane fraction. Cerebroside was the major lipid present and dodecyl sulphate gel electrophoresis revealed a complex protein and glycoprotein composition in the whole membrane. A membrane fraction consisting of only the plaque areas was shown to have a simpler protein composition with major polypeptides of apparent Mr 12 000 and 22 000. These may associate to form a 30 000 apparent Mr complex which could represent the individual 'particles' of the dodecameric subunits seen by electron microscopy in the plaque regions.

Normal adult human bladder obtained at cystoscopy has been maintained in long-term organ culture. Several media were tested for their ability to maintain viability and normal tissue morphology. The optimum medium was Ham's F-12 nutrient mixture, supplemented with 10% fetal calf serum, hydrocortisone (1 microgram/ml), and FeSO4, (0.45 microgram/ml). During the first 28 days in vitro, epithelial damage incurred at biopsy and during preparation of the cultures was repaired, and epithelialization of cut stromal surfaces occurred. A wave of cell proliferation was identified by [3H]thymidine autoradiography, 24-h labeling indices rising to a peak of up to 50% on the cut sides of the cultures between 7 and 21 days and falling to 0 to 5% by 21 to 28 days. The regenerating epithelium showed all the normal features of urothelial cell differentiation when examined by scanning and transmission electron microscopy. From 28 days, histology and scanning and transmission electron microscopy showed the cultured urothelium in most cultures to resemble closely that in the normal bladder in vivo, and in this mature state cultures were maintained for 100 days. Urothelium derived from certain patients, although showing normal surface maturation, developed enlarged intercellular spaces or intraepithelial mucin-containing acini. A study of the cytology of cells shed into the medium at different stages in culture showed that culture viability and epithelial differentiation could be monitored easily in long-term culture by this nondestructive means.

A method for preparing replicas of the luminal surface of frozen, unfractured but deep-etched whole bladder tissue using a Bullivant type II device is described. A small piece of glutaraldehyde-fixed (uncryoprotected) rat bladder is rinsed in distilled water, mounted luminal side uppermost on a specimen holder and rapidly frozen by immersion in liquid nitrogen (cooled below its boiling point in a vacuum) or by contact with a copper block at liquid nitrogen temperature. The specimen is processed in the type II device without fracturing and 'deep-etched' by allowing a longer period than usual to elapse before shadowing. The results are assessed with reference to the appearance of the luminal membrane in standard freeze-fracture replicas, and some preliminary observations on the structure of the normal luminal membrane and its counterpart in bladder tumours are presented.

Some biochemical and ultrastructural changes induced in the livers of rats treated with N-nitrosomorpholine are described and compared with parallel observations in rats given dimethyl- or diethylnitrosamine. Hepatotoxic doses of the nitrosamines caused inhibition of incorporation of [14C]leucine into hepatic proteins, accompanied by progressive disaggregation of polysomes which paralleled the known time course of metabolism of each compound. Dimethylnitrosamine (DMN) and N-nitrosomorpholine (NM) inhibited incorporation of [14C]orotate into liver RNA but diethylnitrosamine (DEN) caused a slight stimulation of orotate incorporation. Electron microscopy revealed similar hepatic cytoplasmic changed induced by each nitrosamine, including dilation and degranulation of the rough surfaced endoplasmic reticulum and subsequent increase of the smooth endoplasmic reticulum. Nuclear changes differed with each compound, N-nitrosomorpholine having more marked effects than either dialkyl compound. The results are discussed with particular reference to the metabolism of N-nitrosomorpholine in the liver.

A sensitive rat model has been designed to detect potential weak bladder carcinogens or co-carcinogens. The test compound is given to animals which have received a single initiating, but non-carcinogenic, dose of N-methyl-N-nitrosourea (MNU). The model has been used to investigate two compounds currently under suspicion as weak bladder carcinogens, namely sodium saccharin and sodium cyclamate, and one compound known to be cytotoxic but not carcinogenic for the bladder epithelium namely cyclophosphamide. For comparison, these three compounds were also tested as solitary carcinogens in animals not pre-treated with MNU. At the very high dose levels used, sodium saccharin and sodium cyclamate were weak solitary carcinogens producing 4/253 and 3/228 bladder tumours respectively, and the first of these tumours did not appear for more than 80 weeks. When tested in the MNU/rat model more than half the animals receiving either sodium saccharin or sodium cyclamate developed bladder tumours from 10 weeks onwards. By contrast, cyclophosphamide failed to produce any tumours when tested either as a solitary carcinogen or in the MNU/rat model. It must be emphasized that the doses of saccharin and cyclamate used were far higher than those consumed by man, including diabetics, and these results should not be directly extrapolated to man without careful consideration of many other factors including negative epidemiological findings. The theoretical basis of the model is discussed and also the relevance, in terms of environmental human exposure, of detecting compounds which have a synergistic effect with other known bladder carcinogens. It appears that this model can be used to detect a carcinogenic or co-carcinogenic potential in compounds which are organotropic for the bladder more rapidly and with fewer animals than if the compounds are tested as solitary carcinogens by more conventional methods. It is suggested that it could be used to detect those compounds which require further investigation.