A case report: Pharmacology and resistance patterns of three generations of ALK inhibitors in metastatic inflammatory myofibroblastic sarcoma.

BACKGROUND: Little exists currently in research about the mechanisms of resistance of ALK inhibitors in inflammatory myofibroblastic sarcoma. It is known, however, that ALK gene rearrangements are common in inflammatory myofibroblastic tumors, similar to non-small cell lung cancer. In roughly 50% of inflammatory myofibroblastic tumors, gene rearrangement has been found to occur on chromosome 2 at band 2p23. In non-small cell lung cancer, it has been shown that about a third of patients who progress on the first generation ALK inhibitor, crizotinib develops mutations in the ALK kinase domain. The remaining two-thirds of patients tend to develop amplification of ALK or activation of alternative signaling pathways. Chromoplexy has also been described as a mechanism of resistance, where multiple closed chain rearrangements cause loss-of-function of tumor suppressor genes and gain-in-function of oncogenic fusions. Partner genes that have been identified in IMTs are tropomyosin 3 (TPM3), tropomyosin 4 (TPM4), clathrin heavy chain (CLTC), Ran-binding protein 2 (RANBP2), cysteinyl-tRNA synthetase (CARS), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), and SEC31L1. All are active promoters for the fusion gene, in response to NPM binding. Several inflammatory myofibroblastic tumor case reports indicated that fusion of ALK and RANBP2 led to a more aggressive clinical course. Although the majority of inflammatory myofibroblastic tumor case reports have utilized first and second generation ALK inhibitors, all generations of ALK inhibitors have demonstrated some ability to impair disease progression and extend life expectancy. However, at some point in the course of therapy with each generation of ALK inhibitor, resistance ultimately developed. In order to better understand the pharmacology and resistance patterns behind three generations of ALK inhibitors, we sought to examine a patient with metastatic anaplastic lymphoma kinase-1-rearranged inflammatory myofibroblastic sarcoma to the brain. We also explored the similarities and differences of this clinical case to other inflammatory myofibroblastic sarcoma case reports involving the use of ALK inhibitors. CASE REPORT: A rare case of pulmonary IMS with ALK-1 gene rearrangement and multiple brain metastases responded to three generations of ALK inhibitors. However, similar to other case reports, due to the development of resistance and recurrence, the patient eventually succumbed to the disease. CONCLUSIONS: ALK inhibitors are beneficial in the temporary prevention of progression of disease in patients with inflammatory myofibroblastic tumors. In this case, due to the inability to reveal the fusion partner in this patient via DNA sequencing, it is unknown exactly if that partner was RANBP2 or another ALK partner gene. Brain biopsy tissue was also unobtainable during sequence of ALK due to risk versus benefit, which would have provided insight as which type of ALK resistance mutations the patient was developing. It is likely that this patient had some form of chromoplexy occurring.

All-Cause Mortality and Progression Risks to Hepatic Decompensation and Hepatocellular Carcinoma in Patients Infected With Hepatitis C Virus.

BACKGROUND: A key question in care of patients with chronic hepatitis C virus (HCV) infection is beginning treatment immediately vs delaying treatment. Risks of mortality and disease progression in "real world" settings are important to assess the implications of delaying HCV treatment. METHODS: This was a cohort study of HCV patients identified from 4 integrated health systems in the United States who had liver biopsies during 2001-2012. The probabilities of death and progression to hepatocellular carcinoma, hepatic decompensation (hepatic encephalopathy, esophageal varices, ascites, or portal hypertension) or liver transplant were estimated over 1, 2, or 5 years by fibrosis stage (Metavir F0-F4) determined by biopsy at beginning of observation. RESULTS: Among 2799 HCV-monoinfected patients who had a qualifying liver biopsy, the mean age at the time of biopsy was 50.7 years. The majority were male (58.9%) and non-Hispanic white (66.9%). Over a mean observation of 5.0 years, 261 (9.3%) patients died and 34 (1.2%) received liver transplants. At 5 years after biopsy, the estimated risk of progression to hepatic decompensation or hepatocellular carcinoma was 37.2% in stage F4, 19.6% in F3, 4.7% in F2, and 2.3% in F0-F1 patients. Baseline biopsy stage F3 or F4 and platelet count below normal were the strongest predictors of progression to hepatic decompensation or hepatocellular carcinoma. CONCLUSIONS: The risks of death and progression to liver failure varied greatly by fibrosis stage. Clinicians and policy makers could use these progression risk data in prioritization and in determining the timing of treatment for patients in early stages of liver disease.

Association between Smoking and Uveitis: Results from the Pacific Ocular Inflammation Study.

PURPOSE: To assess whether cigarette smoking is associated with the development of uveitis in a population-based setting. DESIGN: Retrospective, population-based, case-control study. PARTICIPANTS: Patients aged ≥ 18 years who were seen at a Kaiser Permanente Hawaii clinic between January 1, 2006, and December 31, 2007. Analysis included 100 confirmed incident uveitis cases, 522 randomly selected controls from the general Kaiser Hawaii population, and 528 randomly selected controls from the Kaiser Hawaii ophthalmology clinic. METHODS: International Classification of Diseases, 9th revision (ICD-9), diagnosis codes were used to identify possible uveitis cases. A uveitis fellowship-trained ophthalmologist then conducted individual chart review to confirm case status. Multivariate logistic regression models were used to evaluate the association between smoking and uveitis, adjusting for age, sex, race, and socioeconomic status. MAIN OUTCOME MEASURES: Development of uveitis. RESULTS: Current smokers had a 1.63 (95% confidence interval [CI], 0.88-3.00; P = 0.12) and 2.33 (95% CI, 1.22-4.45; P = 0.01) times greater odds of developing uveitis compared with those who never smoked using the general and ophthalmology control groups, respectively. The association was even stronger with noninfectious uveitis, which yielded odds ratios of 2.10 (95% CI, 1.10-3.99; P = 0.02) and 2.96 (95% CI, 1.52-5.77; P = 0.001) using the general and ophthalmology control groups, respectively. CONCLUSIONS: Cigarette smoking is significantly associated with new-onset uveitis within a population-based setting. The association was stronger for noninfectious uveitis. Given the well-established risks of smoking with regard to other inflammatory disorders, these results reaffirm the importance of encouraging patients to avoid or cease smoking.

Incidence of herpes zoster ophthalmicus: results from the Pacific Ocular Inflammation Study.

PURPOSE: To provide a population-based estimate of the incidence of herpes zoster ophthalmicus (HZO) with comparisons across racial, sex, and age groups, as well as to estimate the frequency of postherpetic neuralgia (PHN). DESIGN: Retrospective, population-based cohort study. PARTICIPANTS: All patients enrolled in the Kaiser Permanente Hawaii health plan during the study period (N = 217 061). METHODS: All patient encounters between January 1, 2006, and December 31, 2007, in the electronic medical record of Kaiser Permanente Hawaii were queried for International Classification of Diseases, 9th edition (ICD-9) codes corresponding to HZO. Charts were reviewed to confirm a diagnosis of HZO and to collect information about specific ocular manifestations. Demographic data and information on PHN were collected electronically. Incidence rates were calculated per 100 000 person-years for the entire population and for age-, sex-, and race-specific subgroups. MAIN OUTCOME MEASURES: Clinical diagnosis of HZO during the study period. RESULTS: A total of 134 cases of HZO were identified in this population of 217 061 people. The overall incidence was 30.9 per 100 000 person-years (95% confidence interval [CI], 25.9-36.6). The incidence rate for the population aged ≥65 years was 104.6 per 100 000 person-years (95% CI, 79.0-135.9), approximately 5 times the remainder of the population (P < 0.001). The most common manifestation of HZO was dermatitis, followed by keratitis and conjunctivitis. The incidence of HZO for Pacific Islanders was 19.0 per 100 000 person-years (95% CI, 12.4-28.3), which was significantly lower than the rate for non-Pacific Islanders (P = 0.007). Twenty-one percent of patients with HZO developed PHN. Older age and HZO with keratitis, conjunctivitis, or uveitis were found to be risk factors for PHN. CONCLUSIONS: This study provides a population-based estimate of HZO and highlights differences across various age and racial groups. It also suggests that demographic characteristics may be useful in determining the risk of developing HZO.

Metastatic Anaplastic Lymphoma Kinase-1 (ALK-1)-Rearranged Inflammatory Myofibroblastic Sarcoma to the Brain with Leptomeningeal Involvement: Favorable Response to Serial ALK Inhibitors: A Case Report.

BACKGROUND ALK gene rearrangements as oncogenic drivers have been described in many cancers, including inflammatory myofibroblastic sarcoma (IMS). The first-generation ALK inhibitor was limited in its ability to cross the blood-brain-barrier to treat brain metastasis. Drug-resistance invariably develops over time in ALK-rearranged tumors, which leads to disease progression. The newer generations of ALK inhibitors are designed to have higher potency in ALK inhibition and improved CNS penetration. CASE REPORT We report a rare case of pulmonary IMS with ALK-1 gene rearrangement and multiple brain metastases as initial presentation. After the primary lung tumor and the larger brain metastases were resected, control of residual CNS disease and subsequent progression and CNS spread was achieved with favorable clinical response by all three generations of ALK inhibitors. CONCLUSIONS ALK inhibitors may be an effective therapy for this rare and unusual form of ALK-1-rearranged cancer, even in the presence of multifocal CNS metastases with leptomeningeal involvement.

Association between statin use and uveitis: results from the Pacific Ocular Inflammation study.

PURPOSE: To assess whether there is a protective association between statin use and uveitis diagnosis. DESIGN: Retrospective, population-based case-control study. METHODS: Medical records of all patients in the Kaiser Permanente Hawaii health plan between January 1, 2006 and December 31, 2007 (N = 217 061) were searched electronically for International Classification of Diseases, 9th Revision, diagnosis codes related to uveitis. Chart review was done to confirm incident uveitis diagnosis during the study period. Two control groups were each randomly selected at a 5:1 ratio to cases, and controls were assigned an index date to match their respective case diagnosis date. One control group was selected from the general Kaiser Permanente Hawaii population that had at least 1 healthcare visit during the study period. Another control group was selected from the population of Kaiser Permanente Hawaii members who had at least 1 visit to the ophthalmology clinic during the study period. Statin use was defined as filling a prescription for statin medication in the year prior to the diagnosis or index date based on an electronic search of the Kaiser Permanente Hawaii pharmacy database for Generic Product Identification codes. A conditional logistic regression model with clinical diagnosis of uveitis as the outcome was used to assess the relationship between statin use and uveitis. RESULTS: One hundred eight incident cases of uveitis were identified. Nineteen percent of uveitis patients had used statin medication in the year prior to diagnosis compared to 30% of patients in the general Kaiser population control (P = .03) and 38% of patients in the ophthalmology clinic control (P < .001). Using the general Kaiser population control and adjusting for age, sex, race, and autoimmune diseases, the odds of a statin user developing uveitis were 48% less than the odds of a non-statin user developing uveitis (OR: 0.52, 95% CI: 0.29-0.94, P = .03). Similarly, the odds of developing uveitis were 33% less for statin users compared to non-statin users (OR: 0.67, 95% CI: 0.38-1.19, P = .17) when adjusting for these factors and using the ophthalmology clinic control group. CONCLUSIONS: Statin use may be protective against the development of uveitis. Several anti-inflammatory and immunomodulatory mechanisms may explain this association.

Association between atopy and herpetic eye disease: results from the pacific ocular inflammation study.

IMPORTANCE: Immune dysregulation in patients with atopy has been hypothesized to increase susceptibility to viral infections. Herpetic eye disease (due to herpes simplex and herpes zoster) is a significant cause of visual impairment, and data on an association between this sight-threatening disease and atopy are limited. OBJECTIVE: To assess the association between atopy and herpetic eye disease, including herpes simplex virus (HSV) ocular disease and herpes zoster ophthalmicus (HZO). DESIGN, SETTING, AND PARTICIPANTS: Retrospective, population-based case-control study from January 1, 2006, through December 31, 2007, at Kaiser Permanente Hawaii, a multispecialty managed care organization serving approximately 15% of the general Hawaiian population. Participants were 217,061 patients enrolled in the Kaiser Permanente Hawaii health plan during the study period. MAIN OUTCOMES AND MEASURES: Clinical diagnosis of HSV ocular disease or HZO during the study period determined by an initial search of the electronic medical record of Kaiser Permanente Hawaii and then confirmed through individual medical record review by a uveitis and cornea fellowship-trained ophthalmologist. Atopic disease status was determined based on International Classification of Diseases, Ninth Revision codes for patients with HSV ocular disease or HZO and 2 control groups, each randomly selected at a 4:1 ratio of controls to cases. RESULTS: One hundred fourteen patients with HSV ocular disease and 137 patients with HZO were identified. Using the age- and sex-matched controls, patients who had atopy had a 2.6-fold (95% CI, 1.6-4.2; P < .001) higher odds of having HSV ocular disease compared with patients who did not have atopy. Similarly, patients with atopy had a 1.8-fold (95% CI, 1.2-2.8; P = .01) increased odds of having HZO. Patients with 2 or more atopic conditions had an 8.9-fold (95% CI, 3.5-22.6; P < .001) higher odds of having HSV ocular disease and a 2.9-fold (95% CI, 1.1-7.7; P = .04) higher odds of having HZO. CONCLUSIONS: AND RELEVANCE The association between atopy and herpetic eye disease may be explained by various factors, including immunologic dysfunction in patients with atopy. Clinically, these results could help support the diagnosis of herpetic eye disease in these patients.

Incidence and prevalence of uveitis: results from the Pacific Ocular Inflammation Study.

IMPORTANCE: Uveitis is responsible for a significant proportion of legal blindness in the United States. Currently, there are few population-based reports characterizing the epidemiology of uveitis. OBJECTIVE: To ascertain the incidence and prevalence of uveitis in a Hawaiian population and compare these estimates with those from prior population-based studies. DESIGN: Retrospective, population-based cohort study conducted from January 1, 2006, to December 31, 2007. SETTING: Kaiser Permanente Hawaii, a multispecialty managed care organization serving approximately 15% of the general Hawaiian population with locations throughout the Hawaiian islands. PARTICIPANTS: All patients enrolled in the Kaiser Permanente Hawaii health plan during the study (N = 217,061). MAIN OUTCOMES AND MEASURES: Clinical diagnosis of uveitis, either incident or prevalent, during the study determined by an initial search of the electronic medical record database of Kaiser Permanente Hawaii for uveitis-associated International Classification of Diseases, Ninth Revision diagnosis codes and subsequently confirmed through individual record review by a uveitis specialist. RESULTS: Of 217,061 eligible patients, 872 were identified using International Classification of Diseases, Ninth Revision codes and 224 cases of uveitis were confirmed. The overall uveitis incidence rate was 24.9 cases per 100,000 person-years. The annual prevalence rates for 2006 and 2007 were 57.5 and 58.0 per 100,000 persons, respectively. No difference in incidence rate was found by sex (P = .63), but female patients had a higher prevalence (P = .008). Incidence and prevalence increased with older age (P < .001 for incidence and prevalence). Pacific Islanders had a lower prevalence rate than non-Pacific Islanders (2006: P = .09, 2007: P = .04), while white individuals had a higher prevalence rate than nonwhite individuals (2006: P = .07, 2007: P = .01). CONCLUSIONS AND RELEVANCE: The incidence and prevalence of uveitis in this population were much lower than in the Northern California Epidemiology of Uveitis Study, but similar to the Northwest Veterans Affairs Study. The results of this study highlight incidence and prevalence estimates in a new population and provide novel comparisons by race. These differences by race raise questions regarding the effects of genetic and environmental influences on the pathophysiology of uveitis.

Incidence of scleritis and episcleritis: results from the Pacific Ocular Inflammation Study.

PURPOSE: To ascertain the incidence of scleritis and episcleritis in a Hawaiian population and describe variations by age, sex, and race. DESIGN: Retrospective, population-based cohort study. METHODS: All electronic medical records for enrollees in Kaiser Permanente Hawaii (n = 217,061) from January 1, 2006 to December 31, 2007 were searched for International Classification of Diseases, 9th Edition (ICD-9) codes associated with ocular inflammation. Chart review was conducted to verify a clinical diagnosis of scleritis or episcleritis. Confirmed cases were used to calculate incidence rates per 100,000 person-years. Ninety-five percent confidence intervals (CI) were calculated for each incidence rate, including age-, sex-, and race-specific rates, using bias-corrected Poisson regression. To assess for confounding, a multivariate analysis adjusting for age, sex, and race was also performed. RESULTS: Of 217,061 eligible patients, 17 incident scleritis cases and 93 incident episcleritis cases were confirmed. The overall incidence rates of scleritis and episcleritis were 4.1 (95% CI: 2.6-6.6) and 21.7 (95% CI: 17.7-26.5) cases per 100,000 person-years, respectively. Women were overrepresented among scleritis patients (P = .049). Pacific Islanders were the most underrepresented racial group among cases of scleritis and episcleritis (P = .006, P = .001). Blacks had the highest incidence of scleritis (P = .004). CONCLUSIONS: These results provide a population-based estimate of the incidence of scleritis and episcleritis in a diverse population and highlight differences in patients' demographic characteristics. Differences in incidence by sex and race raise questions about genetic and environmental influences on the development of these conditions.