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1.  Acute liver toxicity with ifosfamide in the treatment of sarcoma: a case report 
Ifosfamide is a chemotherapy agent infrequently associated with liver toxicity. To the best of our knowledge, this report is the first to describe serious liver toxicity associated with ifosfamide used in combination with doxorubicin that caused acute but fully reversible liver failure and encephalopathy. This report reviews the possible mechanisms by which ifosfamide causes this adverse effect.
Case report
A 61-year-old Caucasian woman who presented with an inoperable right neck mass due to synovial sarcoma was treated with standard-dose ifosfamide and doxorubicin. Within 24 hours of completing the first cycle of chemotherapy, she developed significant derangements in liver function, with a 250-fold increase in transaminase and associated synthetic function impairment and encephalopathy. No other causes of liver failure were identified. Both biochemical tests and encephalopathy were reversed after supportive management and treatment with N-acetylcysteine. No liver toxicity was observed with subsequent cycles of chemotherapy with doxorubicin alone.
This case highlights the possibility that chemotherapy agents can cause rare and idiosyncratic toxicities, so physicians must be vigilant for drug reactions, especially when patients do not respond to usual treatment.
PMCID: PMC3117822  PMID: 21569511
2.  An unexpected cause of deranged liver function: pyogenic liver abscess 
JRSM Short Reports  2011;2(1):4.
PMCID: PMC3031185  PMID: 21286227
3.  Ileocaecal recurrence of Merkel cell carcinoma of the skin: a case report 
Merkel cell carcinoma is an uncommon skin malignancy that has a high propensity for metastatic spread. A systematic literature search identified 17 cases describing metastasis to the gastrointestinal tract, with 7 cases involving the small or large bowel. To the best of our knowledge, this is the only case described of Merkel cell carcinoma metastasising to the ileocaecal valve.
Case presentation
We present a 74-year-old Filipino woman diagnosed with Merkel cell carcinoma of the skin with regional node involvement. Following excision and radiotherapy, the tumour recurred with metastasis to the ileocaecal valve. The patient died 28 months after the initial diagnosis.
The prognosis of metastatic Merkel cell carcinoma is poor. Currently the optimal management for metastatic disease is unclear and lacks a firm evidence base due to the small number of cases reported.
PMCID: PMC2838912  PMID: 20181112
4.  Human CHN1 mutations hyperactivate α2-chimaerin and cause Duane’s retraction syndrome 
Science (New York, N.Y.)  2008;321(5890):839-843.
The RacGAP molecule α2-chimaerin is implicated in neuronal signaling pathways required for precise guidance of developing corticospinal axons. We now demonstrate that a variant of Duane’s retraction syndrome, a congenital eye movement disorder in which affected individuals show aberrant development of axon projections to the extraocular muscles, can result from gain-of-function heterozygous missense mutations in CHN1 that increase α2-chimaerin RacGAP activity in vitro. A subset of mutations enhances α2-chimaerin membrane translocation and/or α2-chimaerin’s previously unrecognized ability to form a complex with itself. In ovo expression of mutant CHN1 alters the development of ocular motor axons. These data demonstrate that human CHN1 mutations can hyperactivate α2-chimaerin and result in aberrant cranial motor neuron development.
PMCID: PMC2593867  PMID: 18653847
5.  Loss of Caveolin-1 Gene Expression Accelerates the Development of Dysplastic Mammary Lesions in Tumor-Prone Transgenic Mice 
Molecular Biology of the Cell  2003;14(3):1027-1042.
Caveolin-1 is the principal structural component of caveolae microdomains, which represent a subcompartment of the plasma membrane. Several independent lines of evidence support the notion that caveolin-1 functions as a suppressor of cell transformation. For example, the human CAV-1 gene maps to a suspected tumor suppressor locus (D7S522/7q31.1) that is frequently deleted in a number of carcinomas, including breast cancers. In addition, up to 16% of human breast cancers harbor a dominant-negative mutation, P132L, in the CAV-1 gene. Despite these genetic associations, the tumor suppressor role of caveolin-1 still remains controversial. To directly assess the in vivo transformation suppressor activity of the caveolin-1 gene, we interbred Cav-1 (−/−) null mice with tumor-prone transgenic mice (MMTV-PyMT) that normally develop multifocal dysplastic lesions throughout the entire mammary tree. Herein, we show that loss of caveolin-1 gene expression dramatically accelerates the development of these multifocal dysplastic mammary lesions. At 3 wk of age, loss of caveolin-1 resulted in an approximately twofold increase in the number of lesions (foci per gland; 3.3 ± 1.0 vs. 7.0 ± 1.2) and an approximately five- to sixfold increase in the total area occupied by these lesions. Similar results were obtained at 4 wk of age. However, complete loss of caveolin-1 was required to accelerate the appearance of these dysplastic mammary lesions, because Cav-1 (+/−) heterozygous mice did not show any increases in foci development. We also show that loss of caveolin-1 increases the extent and the histological grade of these mammary lesions and facilitates the development of papillary projections in the mammary ducts. Finally, we demonstrate that cyclin D1 expression levels are dramatically elevated in Cav-1 (−/−) null mammary lesions, consistent with the accelerated appearance and growth of these dysplastic foci. This is the first in vivo demonstration that caveolin-1 can function as a transformation suppressor gene.
PMCID: PMC151577  PMID: 12631721
6.  The Royal Free Hospital Score: A Calibrated Prognostic Model for Patients With Cirrhosis Admitted to Intensive Care Unit. Comparison With Current Models and CLIF-SOFA Score 
Prognosis for patients with cirrhosis admitted to intensive care unit (ICU) is poor. ICU prognostic models are more accurate than liver-specific models. We identified predictors of mortality, developed a novel prognostic score (Royal Free Hospital (RFH) score), and tested it against established prognostic models and the yet unvalidated Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) model.
Predictors of mortality were defined by logistic regression in a cohort of 635 consecutive patients with cirrhosis admitted to ICU (1989–2012). The RFH score was derived using a 75% training and 25% validation set. Predictive accuracy and calibration were evaluated using area under the receiver operating characteristic (AUROC) and goodness-of-fit χ2 for the RFH score, as well as for SOFA, Model for End-Stage Liver Disease (MELD), Acute Physiology and Chronic Health Evaluation (APACHE II), and Child-Pugh. CLIF-SOFA was applied to a recent subset (2005–2012) of patients.
In-hospital mortality was 52.3%. Mortality improved over time but with a corresponding reduction in acuity of illness on admission. Predictors of mortality in training set, which constituted the RFH score, were the following: bilirubin, international normalized ratio, lactate, alveolar arterial partial pressure oxygen gradient, urea, while variceal bleeding as indication for admission conferred lesser risk. Classification accuracy was 73.4% in training and 76.7% in validation sample and did not change significantly across different eras of admission. The AUROC for the derived model was 0.83 and the goodness-of-fit χ2 was 3.74 (P=0.88). AUROC for SOFA was 0.81, MELD was 0.79, APACHE II was 0.78, and Child-Pugh was 0.67. In 2005–2012 cohort, AUROC was: SOFA: 0.74, CLIF-SOFA: 0.75, and RFH: 0.78. Goodness-of-fit χ2 was: SOFA: 6.21 (P=0.63), CLIF-SOFA: 9.18 (P=0.33), and RFH: 2.91 (P=0.94).
RFH score demonstrated good discriminative ability and calibration. Internal validation supports its generalizability. CLIF-SOFA did not perform better than RFH and the original SOFA. External validation of our model should be undertaken to confirm its clinical utility.
PMCID: PMC3978197  PMID: 24492755

Results 1-6 (6)