Searching for a needle in a haystack: use of ICD-9-CM codes in drug-induced liver injury

OBJECTIVES: The aim of our study was to compare three search strategies using a computerized administrative database to identify cases of idiosyncratic drug-induced liver injury (DILI) due to amoxicillin/clavulanic acid, phenytoin, valproic acid, and isoniazid. METHODS: In search 1, electronic medical records from patients seen between 1994 and 2004 with an ICD-9-CM code of acute liver injury were identified and cross-searched for the specific drug names in the dictation text. In search 2, all patients with an ICD-9-CM code of drug poisoning/overdose due to one of the four study drugs were identified. In search 3, patients with a poisoning code as well as an acute liver injury code were identified. RESULTS: Review of the records from the 7,395 search 1 patients yielded 51 DILI cases (0.7%). In contrast, the 566 search 2 patients yielded only three DILI cases (0.5%). Finally, search 3 provided the greatest specificity but a low rate of detection with only two patients (3.9%) having DILI due to one of the four drugs. CONCLUSION: Acute liver injury ICD-9-CM codes combined with a text search of the dictated medical record yielded the greatest number of DILI cases but was less specific than crossing acute liver injury and poisoning codes. Use of ICD-9-CM codes to identify rare adverse events like DILI remains problematic and highlights the need for prospective surveillance networks.     

Phosphoprotein pathway mapping: Akt/mammalian target of rapamycin activation is negatively associated with childhood rhabdomyosarcoma survival

Mapping of protein signaling networks within tumors can identify new targets for therapy and provide a means to stratify patients for individualized therapy. Despite advances in combination chemotherapy, the overall survival for childhood rhabdomyosarcoma remains approximately 60%. A critical goal is to identify functionally important protein signaling defects associated with treatment failure for the 40% nonresponder cohort. Here, we show, by phosphoproteomic network analysis of microdissected tumor cells, that interlinked components of the Akt/mammalian target of rapamycin (mTOR) pathway exhibited increased levels of phosphorylation for tumors of patients with short-term survival. Specimens (n = 59) were obtained from the Children's Oncology Group Intergroup Rhabdomyosarcoma Study (IRS) IV, D9502 and D9803, with 12-year follow-up. High phosphorylation levels were associated with poor overall and poor disease-free survival: Akt Ser(473) (overall survival P < 0.001, recurrence-free survival P < 0.0009), 4EBP1 Thr(37/46) (overall survival P < 0.0110, recurrence-free survival P < 0.0106), eIF4G Ser(1108) (overall survival P < 0.0017, recurrence-free survival P < 0.0072), and p70S6 Thr(389) (overall survival P < 0.0085, recurrence-free survival P < 0.0296). Moreover, the findings support an altered interrelationship between the insulin receptor substrate (IRS-1) and Akt/mTOR pathway proteins (P < 0.0027) for tumors from patients with poor survival. The functional significance of this pathway was tested using CCI-779 in a mouse xenograft model. CCI-779 suppressed phosphorylation of mTOR downstream proteins and greatly reduced the growth of two different rhabdomyosarcoma (RD embryonal P = 0.00008; Rh30 alveolar P = 0.0002) cell lines compared with controls. These results suggest that phosphoprotein mapping of the Akt/mTOR pathway should be studied further as a means to select patients to receive mTOR/IRS pathway inhibitors before administration of chemotherapy.     

Orbital Inflammatory Syndrome and Anterior Uveitis: A Case Series

Purpose: To describe four cases of orbital inflammatory syndrome (OIS) with associated anterior uveitis that have presented within 2 years to our practice.

Methods: Charts of patients diagnosed with OIS from June 2013 to May 2015 were reviewed.

Results: Four patients, three children and one adult, presented with orbital swelling, pain, and varying degrees of vision loss. Treatment with intravenous methylprednisolone resulted in significant symptomatic improvement in all cases initially; when symptoms recurred, the patients had evidence of anterior uveitis. With continued systemic therapy and the addition of topical prednisolone, the patients all achieved control of their uveitis and OIS and are well controlled with regular outpatient follow-up.

Conclusions: Reports of OIS-associated with uveitis are relatively rare. The presentation of three pediatric patients and one adult patient to the same practice with OIS and secondary uveitis within a 2-year period may indicate that the association is underreported.     

A Phase II Study of the Efficacy and Safety of Chloroquine in Combination With Taxanes in the Treatment of Patients With Advanced or Metastatic Anthracycline-refractory Breast Cancer

IntroductionChemotherapy eliminates most of the cancer cells except those with potential for self-renewal and tumor initiation, called cancer stem cells (CSCs). Chloroquine, through bioinformatics, was found to be a potential agent to target CSCs. We designed a phase II trial to test the efficacy and safety of chloroquine in combination with taxane or taxane-like chemotherapy agents in patients with advanced or metastatic breast cancer who are refractory to anthracycline-based chemotherapy.Patients and MethodsFemale patients ≥ 18 years of age who had received prior anthracycline chemotherapy were enrolled in this study. Chloroquine 250 mg was given daily orally with either docetaxel or paclitaxel or nab-paclitaxel or ixabepilone every 3 weeks. The maximum number of 3-week cycles allowed was 6. The primary efficacy endpoint was the objective response rate (ORR). The secondary efficacy endpoints included progression-free survival (PFS) and safety analysis.ResultsThirty-eight patients were enrolled in the study, and 31 patients were evaluated for response. The median age was 54.1 years (range, 31.7-78.1 years). The ORR was 45.16% (95% confidence interval [CI], 29.2%-62.2%), which was higher than the expected ORR of 30% (P = .03). Patients were followed for a median of 25.4 months and experienced a median PFS of 12.4 months (95% CI, 4.9-24.6 months) and a median OS of 25.4 months (95% CI, 13.7-83.5 months). The combination was well-tolerated, with only 13.15% of patients experiencing grade ≥ 3 adverse events.ConclusionA combination of chloroquine with taxane or taxane-like chemotherapy was efficacious in patients with locally advanced or metastatic breast cancer with prior anthracycline-based chemotherapy.