Genomic Profiling of Intrahepatic Cholangiocarcinoma: Refining Prognosis and Identifying Therapeutic Targets

Background

The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection.

Methods

Multiplexed mutational profiling was performed using nucleic acids that were extracted from 200 resected ICC tumor specimens from 7 centers. The frequency of mutations was ascertained and the effect on outcome was determined.

Results

The majority of patients (61.5 %) had no genetic mutation identified. Among the 77 patients (38.5 %) with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5 %: IDH1 (15.5 %) and KRAS (8.6 %). Other genetic mutations were identified in very low frequency: BRAF (4.9 %), IDH2 (4.5 %), PIK3CA (4.3 %), NRAS (3.1 %), TP53 (2.5 %), MAP2K1 (1.9 %), CTNNB1 (0.6 %), and PTEN (0.6 %). Among patients with an IDH1-mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 (4 %). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (odds ratio 2.75), while KRAS-mutant tumors were more likely to be associated with R1 margin (odds ratio 6.51) (both P < 0.05). Although clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis.

Conclusions

Most somatic mutations in resected ICC tissue are found at low frequency, supporting a need for broad-based mutational profiling in these patients. IDH1 and KRAS were the most common mutations noted. Although certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly affect long-term prognosis.     

"Were-wolf" cutaneous tuberculosis

Lupus vulgaris is a variant of cutaneous tuberculosis. Its more destructive and mutilating clinical forms have become rarer in consonance of a general decline of cutaneous tuberculosis. It is rarely seen now in developed countries due to stringent control measures, improved quality of living and effective therapeutic regimens. Misdiagnosis, neglect, or late diagnosis may result in severe, ulcerative and mutilating "wolf eaten" skin lesions.This paper describes four such cases of "were-wolf" cutaneous tuberculosis. Early diagnosis and treatment is important to prevent much of the disfigurement.     

Dapsone for chronic idiopathic thrombocytopenic purpura in children and adults--a report on 90 patients

Data on 90 patients (55 adults and 35 children) with chronic idiopathic thrombocytopenic purpura (ITP) and a platelet count of <50 x 10(9)/L treated with dapsone at a dose of 1-2 mg/kg/d are presented. A response was observed in 57 (63.3%) patients. The average time for response was 3.5 months (range 1-9) and the average duration of treatment with dapsone was 10.4 months (range 4-14). Overall response rates of 65.7% and 61.8% were observed in children and adults respectively. Side effects requiring discontinuation of therapy were observed in three (2%) patients. These results demonstrate that dapsone is an effective, inexpensive and well-tolerated treatment for chronic ITP, in both children and adults and could be considered for patients who fail steroid therapy.     

Surgery for hemophilia in developing countries

Surgical interventions in patients with hemophilia (PWH) in the developing world are difficult in the setting of limited availability of factor concentrates. Although the adequacy of international guidelines for factor concentrate prophylaxis for PWH undergoing surgery has been established, frequently it is not practical in the developing world. These recommendations were not established based on large clinical trials and fail to define the safe lower limit of factor concentrate prophylaxis for surgery. The need to define these lower limits is essential in the developing world so that the limited resources may be used optimally for the cohort of PWH. There are limited data from the developing world with regard to PWH undergoing surgical procedures. In this article, we outline experience from our institution, a tertiary referral center for hemophilia care in India. We trace the basis on which our current factor concentrate prophylaxis regimen (which is lower than that recommended internationally) was established. In our experience our low-dose protocols are effective, reduce factor consumption by one third, and are not associated with a significantly increased risk of delayed hemorrhage. We hope that this experience will form a framework on which guidelines can be established for developing countries.     

Novel PEGylated Basal Insulin LY2605541 Has a Preferential Hepatic Effect on Glucose Metabolism

The impact of the novel basal insulin LY2605541 (LY) on hepatic and nonhepatic glucose uptake (non-HGU) was evaluated. Conscious dogs underwent euglycemic clamps with tracer and hepatic balance measurements. Clamp period infusions were peripheral venous regular insulin (0.1 nmol ⋅ kg⁻¹ ⋅ h⁻¹ [control], n = 6) or LY (bolus [nmol/kg], continuous [nmol ⋅ kg⁻¹ ⋅ h⁻¹]: 0.5, 0.5 [n = 6]; 0.375, 0.375 [n = 5]; 0.25, 0.25 [n = 4]), somatostatin, and glucose, as well as intraportal glucagon (basal). During the clamp, the dogs switched from net hepatic glucose output to uptake (rates reached 2.1 ± 1.2, 0.9 ± 2.1, 8.6 ± 2.3, and 6.0 ± 1.1 µmol ⋅ kg⁻¹ ⋅ min⁻¹ within 5 h in control, LY_0.25, LY_0.375, and LY_0.5, respectively). Non-HGU in LY increased less than in control; the ratio of change from basal in non-HGU to change in net hepatic glucose balance, calculated when glucose infusion rates (GIRs) were ~20 µmol ⋅ kg^-1 ⋅ min⁻¹ in all groups, was higher in control (1.17 ± 0.38) versus LY_0.25 (0.39 ± 0.33), LY_0.375 (−0.01 ± 0.13), and LY_0.5 (−0.09 ± 0.07). Likewise, the change from baseline in glucose R_d-to-R_a ratio was greatest in control (1.4 ± 0.3 vs. 0.6 ± 0.4, 0.5 ± 0.2, and 0.6 ± 0.2 in LY_0.25, LY_0.375, and LY_0.5, respectively). In contrast to exogenously administered human insulin, LY demonstrated preferential hepatic effects, similar to endogenously secreted insulin. Therefore, the analog might reduce complications associated with current insulin therapy.     

Fulminant hepatitis due to human adenovirus

Purpose

To describe the demographics, clinical manifestations, treatment and outcomes of patients with human adenovirus (HAdV) hepatitis.

Methods

A case of fulminant HAdV hepatitis in a patient with chronic lymphocytic leukemia receiving rituximab and fludarabine is described. We conducted a comprehensive review of the English-language literature through May, 2012 in search of definite cases of HAdV hepatitis.

Results

Eighty-nine cases were reviewed. Forty-three (48 %) were liver transplant recipients, 19 (21 %) were bone marrow transplant recipients, 11 (12 %) had received chemotherapy, five (6 %) had severe combined immunodeficiency, four (4 %) were HIV infected, two had heart transplantation, and two were kidney transplant recipients. Ninety percent (46/51) of patients presented within 6 months following transplantation. Fever was the most common initial symptom. Abdominal CT scan revealed hypodense lesions in eight of nine patients. Diagnosis was made by liver biopsy in 43 (48 %), and on autopsy in 46 (52 %). The HAdV was isolated at other sites in 54 cases. Only 24 of 89 patients (27 %) survived: 16 whose immunosuppression was reduced, six with liver re-transplantation, and two who received cidofovir and intravenous immunoglobulin.

Conclusion

HAdV hepatitis can manifest as a fulminant illness in immunocompromised hosts. Definitive diagnosis requires liver biopsy. Early consideration of a viral etiology, reduction in immunosuppression, and liver transplantation can be potentially life-saving.