A 59-Year-Old Man With Chronic Kidney Disease After Kidney Transplantation Presents With Chronic Dyspnea.

CASE PRESENTATION: A 59-year-old man presented to the ED with a chief complaint of shortness of breath. His past medical history was significant for end-stage renal disease secondary to lithium toxicity, immunosuppression subsequent to cadaveric renal transplantation, bipolar disorder, and hypertension. His shortness of breath had begun 6 months previously and was initially intermittent; it then progressed to constant shortness of breath over the few weeks before presentation. He had no fever, hemoptysis, or chest pain. The patient was admitted to hospital for further evaluation.

Multiple Myeloma Presenting as Acute Liver Failure.

Liver failure is rarely caused by multiple myeloma (MM). We present an unusual case of MM initially presenting as acute liver injury. A 79-year-old man with new-onset fatigue, decreased appetite, and no history of liver disease was found to have evidence of hepatic decompensation. Liver biopsy demonstrated diffuse plasma cell infiltration, and MM was confirmed with bone marrow biopsy. Chemotherapy was initiated, but the patient decompensated and died due to respiratory failure. MM should be considered on the differential for acute decompensated liver disease. Hepatic involvement of MM at presentation is a poor prognostic indicator, and prompt initiation of treatment can be life-saving.

Nuclear Imaging to Detect Diaphragmatic Perforation as a Rare Complication of Microwave Ablation.

Acquired diaphragmatic perforation leading to massive hepatic hydrothorax and respiratory failure is a rare complication of microwave ablation (MWA) of hepatocellular carcinoma (HCC). Imaging modalities to detect pleuroperitoneal communication remain poorly described. We report a nuclear imaging technique used to efficiently diagnose and locate diaphragmatic defects. A 57-year-old male with cirrhosis and HCC presented with respiratory distress after undergoing MWA of a HCC lesion. He was admitted to the intensive care unit for noninvasive positive pressure ventilator support. Chest radiography revealed a new large right pleural effusion. Large-volume thoracentesis was consistent with hepatic hydrothorax. The fluid reaccumulated within 24 hours; therefore an acquired diaphragmatic perforation induced by the ablation procedure was suspected. To investigate, 99mTechnetium-labeled albumin was injected into the peritoneal cavity. The tracer accumulated in the right hemi thorax almost immediately. The patient then underwent transjugular intrahepatic portosystemic shunting in efforts to relieve portal hypertension and decrease ascites volume. Unfortunately, the patient deteriorated and expired after few days. Although diaphragmatic defects develop in cirrhotic patients, such small fenestrations do not normally lead to rapid development of life-threatening pleural effusion. MWA procedures can cause large diaphragmatic defects. Immediate detection of this complication is essential for initiating early intervention.

Distinct genetic alterations occur in ovarian tumor cells selected for combined resistance to carboplatin and docetaxel.

BACKGROUND: Current protocols for the treatment of ovarian cancer include combination chemotherapy with a platinating agent and a taxane. However, many patients experience relapse of their cancer and the development of drug resistance is not uncommon, making successful second line therapy difficult to achieve. The objective of this study was to develop and characterize a cell line resistant to both carboplatin and docetaxel (dual drug resistant ovarian cell line) and to compare this cell line to cells resistant to either carboplatin or docetaxel. METHODS: The A2780 epithelial endometrioid ovarian cancer cell line was used to select for isogenic carboplatin, docetaxel and dual drug resistant cell lines. A selection method of gradually increasing drug doses was implemented to avoid clonal selection. Resistance was confirmed using a clonogenic assay. Changes in gene expression associated with the development of drug resistance were determined by microarray analysis. Changes in the expression of selected genes were validated by Quantitative Real-Time Polymerase Chain Reaction (QPCR) and immunoblotting. RESULTS: Three isogenic cell lines were developed and resistance to each drug or the combination of drugs was confirmed. Development of resistance was accompanied by a reduced growth rate. The microarray and QPCR analyses showed that unique changes in gene expression occurred in the dual drug resistant cell line and that genes known to be involved in resistance could be identified in all cell lines. CONCLUSIONS: Ovarian tumor cells can acquire resistance to both carboplatin and docetaxel when selected in the presence of both agents. Distinct changes in gene expression occur in the dual resistant cell line indicating that dual resistance is not a simple combination of the changes observed in cell lines exhibiting single agent resistance.

Induction of 1C aldoketoreductases and other drug dose-dependent genes upon acquisition of anthracycline resistance.

OBJECTIVES: Recent studies suggest that tumor cells overexpressing aldoketoreductases (AKRs) exhibit increased resistance to DNA damaging agents such as anthracyclines. AKRs may induce resistance to the anthracycline doxorubicin by catalyzing its conversion to the less toxic 13-hydroxy metabolite doxorubicinol. However, it has not been established whether during selection for anthracycline resistance, AKR overexpression in tumor cells can be correlated with the onset or magnitude of drug resistance and with appreciable conversion of anthracyclines to 13-hydroxy metabolites. METHODS AND FINDINGS: Through microarray and quantitative polymerase chain reaction studies involving rigid selection criteria and both correlative discriminate statistics and time-course models, we have identified several genes whose expression can be correlated with the onset and/or magnitude of anthracycline resistance, including AKR1C2 and AKR1C3. Also associated with the onset or magnitude of anthracycline resistance were genes involved in drug transport (ABCB1, ABCC1), cell signaling and transcription (RDC1, CXCR4), cell proliferation or apoptosis (BMP7, CAV1), protection from reactive oxygen species (AKR1C2, AKR1C3, FTL, FTH, TXNRD1, MT2A), and structural or immune system proteins (IFI30, STMN1). As expected, doxorubicin-resistant and epirubicin-resistant cells exhibited higher levels of doxorubicinol than wild-type cells, although at insufficient levels to account for significant drug resistance. Nevertheless, an inhibitor of Akr1c2 (5beta-cholanic acid) almost completely restored sensitivity to doxorubicin in ABCB1-deficient doxorubicin-resistant cells, while having no effect on ABCB1-expressing epirubicin-resistant cells. CONCLUSION: Taken together, we show for the first time that a variety of genes (particularly redox genes such as AKR1C2 and AKR1C3) can be temporally and causally correlated with the acquisition of anthracycline resistance in breast tumor cells.