Report of Cholangiocarcinoma With Transheterozygous BRCA1 and BRCA2 Co-mutation.

Cholangiocarcinoma is an aggressive malignancy involving the epithelial cells of the intrahepatic, perihilar, or extrahepatic biliary tree. It is a disease that is often diagnosed late in its course and progresses quickly. Identifying genomic mutations may provide an important utility in predicting disease course and individualizing therapy for these patients. Mutations in BRCA1 or BCRCA2 genes have been increasingly documented in hepatobiliary malignancies, but they remain a relatively uncommon occurrence. Co-mutations in both BRCA1 and BRCA2 genes are even rarer, with no previously documented reports to our knowledge of BRCA co-positivity in a patient with a hepatobiliary malignancy. We present a case of a patient with cholangiocarcinoma found to have mutations in both BRCA1 and BRCA2 genes.

Phase II study of denileukin diftitox for previously treated indolent non-Hodgkin lymphoma: final results of E1497.

Denileukin diftitox (DD) is approved for treatment of CD-25 expressing cutaneous T-cell lymphomas (CTCL). Initial studies of DD demonstrated responses in patients with B-cell non-Hodgkin lymphoma (NHL). This phase II trial evaluated response rate (RR) and tolerability of DD in this population. Patients were stratified into two arms: those with NHL expressing > or =20% IL-2R (IL-2R+) or <20% IL-2R (IL-2R-). DD was dosed at 18 microg/kg/day for 5 days every 21 days. Corticosteroid pre-medication was not allowed. Thirty-five patients of a planned 77 accrued due to closure for slow accrual. This report is on 29 patients (18 males) with indolent B-cell NHL (11 IL-2R+ and 18 IL-2R-). Histologic subtypes included small lymphocytic (SLL) (8 patients) and follicular grade I/II lymphoma (21 patients). Patients received a median of three prior regimens, including rituximab in 76%. Three partial responses were observed (RR 10%). The RR for the IL-2R- and IL-2R+ patients was 11% and 9%, respectively. Of 8 patients with SLL, 2 responded. Toxicities were generally grade I - II and transient but 1 patient experienced a fatal thrombo-embolism. Therapy with DD is tolerable and modest efficacy was observed in SLL subtype. Measured IL-2R status did not correlate with efficacy.

Classical Hodgkin's lymphoma presenting with tongue involvement: a case report and review of the literature.

We report an unusual case of mixed cellularity classical Hodgkin's lymphoma with prominent involvement of the base of the tongue at diagnosis. In situ hybridization findings for Epstein-Barr virus were positive. Waldeyer's ring involvement by Hodgkin's lymphoma is uncommon with < 200 cases reported in the English literature and only 5 previous reports of Hodgkin's lymphoma involving the tongue.

Chemotherapy dosing in the setting of liver dysfunction.

Advanced cancer in the setting of liver dysfunction poses a dilemma for physicians, as many cancer chemotherapeutic agents undergo hepatic metabolism. Most cytotoxic drugs have a narrow therapeutic index, and the administration of chemotherapy to patients with liver impairment results in complicated safety issues. We present a concise review of cancer chemotherapy dosing in the setting of liver dysfunction. Although caution in treating all patients with hepatic failure is essential, the use of certain agents provokes greater concern than others. Continuous-infusion fluorouracil, capecitabine (Xeloda), mechlorethamine (Mustargen), cyclophosphamide, topotecan (Hycamtin), and oxaliplatin (Eloxatin) appear to be relatively well tolerated. On the contrary, taxanes, vinca alkaloids, irinotecan (Camptosar), and anthracyclines may cause unacceptable toxicity if administered to patients with poor hepatic function. For many anticancer agents, the paucity of data prohibits formal dosing recommendations, and most guidelines remain empiric.

Elucidation of the Wide Range of Reaction Pathways That Accompany the Electrochemical Oxidation of cis,mer-[Mn(CO)(2)(eta(1)-dpm)(eta(2)-dpm)X] (dpm = Ph(2)PCH(2)PPh(2); X = Cl, Br).

The electrochemical oxidation of cis,mer-[Mn(CO)(2)(eta(1)-dpm)(eta(2)-dpm)Br] (dpm = Ph(2)PCH(2)PPh(2)), or (cis,mer)(0),()()has been examined in dichloromethane (0.1 M Bu(4)NPF(6)) by voltammetric, bulk electrolytic, in situ and ex situ spectroelectrochemical and simulation techniques. On the voltammetric time scale at 20 degrees C, the neutral 18-electron cis,mer Mn(I) species is oxidized to the corresponding 17-electron cation which at slow scan rates isomerizes to the trans cation. Simulations are consistent with a rate constant of 3.1 +/- 0.3 s(-1) for this isomerization process. Monitoring the reaction by in situ IR spectroscopy at low-temperature enables the identification of the nu(CO) bands of all four species ((cis,mer)(0); (cis,mer)(+); (trans)(0); (trans)(+)) in the resultant square reaction scheme that is operative under these thin layer electrolysis conditions. Additionally, 17-electron cis,fac-[Mn(CO)(2)(eta(1)-dpm)(eta(2)-dpm)Br](+) and its 18-electron (cis,fac)(0) counterpart, generated by a redox-induced catalytic isomerization reaction, are detected and characterized by IR spectroscopy (nu(CO)). Room-temperature bulk oxidative electrolysis experiments reveal that the trans cation, generated in bulk solution from the (cis,mer)(+) and (cis,fac)(+) isomers, slowly ejects bromide with a rate constant of 1.6 x 10(-3) s(-1) to form trans-[Mn(CO)(2)(eta(2)-dpm)(2)](+). The equivalent voltammetry in acetonitrile is complicated by an additional competing kinetic step which is attributed to reaction of this cation with the solvent. However, the major product formed upon oxidation at room temperature is still the trans cation. Less detailed studies on the oxidation of cis,mer-[Mn(CO)(2)(eta(1)-dpm)(eta(2)-dpm)Cl] only show significant differences under conditions of bulk electrolysis after trans-[Mn(CO)(2)(eta(2)-dpm)(2)](2+) is formed via expulsion of Cl(-).

A pilot study of denileukin diftitox (DD) in combination with high-dose interleukin-2 (IL-2) for patients with metastatic renal cell carcinoma (RCC).

High-dose (HD) IL-2 is approved to treat renal cell carcinoma (RCC) with modest response rates and significant toxicity. Enhancement of cytotoxic T-cell activity by IL-2 is 1 mechanism of action. IL-2 also stimulates regulatory T lymphocytes (Tregs), which are associated with poor prognosis. Favorable outcomes are associated with greater rebound absolute lymphocyte count (Fumagalli 2003). DD depletes IL-2 receptor (CD25 component) expressing cells. We hypothesized that sequential therapy could complement each other; DD would deplete Tregs so IL-2 could more effectively stimulate proliferation and activity of cytotoxic T lymphocytes. Patients (n=18) received standard HD IL-2 and 1 dose of DD daily for 3 days; periodic flow cytometry and complete blood counts were performed. Group A included 3 patients to assess safety only with DD 6 µg/kg between the IL-2 courses. Group B included 9 patients at 9 µg/kg DD before the IL-2 courses. Group C included 6 patients at 9 µg/kg DD between the IL-2 courses. Efficacy using the RECIST criteria was assessed after the treatment. Fifteen patients from a study of IL-2 without DD served as controls for toxicity comparison and 13 of these for flow cytometry comparisons. No unusual toxicity was noted. For group B/C patients receiving DD, the median decline in Tregs was 56.3% from pre-DD to post-DD (P=0.013). Peak absolute lymphocyte count change from baseline was +9980/µL for group B, +4470/µL for group C, and +4720/µL for the controls (P=0.005 B vs. C). The overall response rate was 5 of 15 (33%); 3 of 9 (33%) and 2 of 6 (33%) for groups B and C, respectively, including 2 patients with sarcomatoid RCC and 1 with earlier sunitinib therapy.

Phase II study of mitoxantrone and ketoconazole for hormone-refractory prostate cancer.

BACKGROUND: Doxorubicin plus ketoconazole has exhibited significant activity in patients with advanced prostate cancer. However, overall and cardiac-specific toxicity was reported to be high. Mitoxantrone has activity similar to that of doxorubicin, is less cardiotoxic, and is widely used to treat prostate cancer. The current study sought to evaluate the toxicity and activity of mitoxantrone plus ketoconazole in a cohort of patients with hormone-refractory prostate cancer. METHODS: Progression after medical or surgical castration and, for those patients receiving antiandrogens, progression after withdrawal was required, as was objective evidence of metastasis, castrate levels of testosterone, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and intact cardiac function. After enrollment onto a multicenter local consortium study, subjects were treated with mitoxantrone at a dose of 12 mg/m2 intravenously every 3 weeks plus continuous oral ketoconazole at a dose of 400 mg 3 times daily and ascorbic acid at a dose of 250 mg. Replacement doses of hydrocortisone were given. RESULTS: For 40 enrolled subjects, the median prostate-specific antigen and ECOG performance status were 68 and 1, respectively, 53% had Gleason scores of 8 to 10, and all had metastasis. Predominant Grade 3/4 toxicities were: neutropenia in 13%, neutropenic fever in 10%, and anemia in 13%. Of 37 evaluable patients, 8% achieved a complete remission (CR) and 62% achieved a partial remission (PR), for a CR plus PR rate of 70%. For soft tissue and bone disease, overall response rates were 13% and 8%, respectively. The median progression-free survival and overall survival were 10 months and 18 months, respectively. CONCLUSIONS: Mitoxantrone plus ketoconazole is well tolerated, is active in hormone-refractory prostate cancer, and should be studied further.

Denileukin diftitox: a concise clinical review.

Denileukin diftitox (DAB389IL-2; Ontak) is a novel recombinant fusion protein approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma. It consists of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptor expressed on malignant cells. This article will review the clinical trials leading to the approval of denileukin diftitox for cutaneous T-cell lymphoma, and discuss the potential future role of this novel drug in patients with both malignant and nonmalignant diseases, including non-Hodgkin's lymphoma, chronic lymphocytic leukemia, solid tumors, psoriasis and graft-versus-host disease.

A review of recent findings involving interleukin-2-based cancer therapy.

PURPOSE OF REVIEW: Highlighted in this review are the important preclinical and clinical updates of interleukin (IL)-2-based cancer immunotherapy that have been published during the last year. RECENT FINDINGS: The review starts with a summary of the preclinical breakthroughs involving IL-2. The authors briefly examine two recent studies that take very different approaches to overcome the toxicities associated with IL-2 therapy. The first involves IL-2 gene transduction into tumor-infiltrating lymphocytes, and the latter discusses the use of a superoxide dismutase mimetic to ameliorate the hypotensive effects of IL-2. This is followed by a discussion of the key roles that T regulatory cells and transforming growth factor-beta have in immunosuppression, and how they interplay with IL-2. Next they review the clinical updates of IL-2 in melanoma, including IL-2 as adjuvant therapy, IL-2-based biochemotherapy, and intralesional IL-2 for soft-tissue metastases. Finally, the authors point out the recent clinical developments of IL-2 in renal cell carcinoma, including high-dose IL-2 as adjuvant therapy, and then focus on its role in the management of metastatic disease. SUMMARY: IL-2 remains a valuable treatment option for patients with metastatic melanoma or renal cell carcinoma. Some of the recent updates in IL-2 therapy address important questions regarding the use of this drug, and others generate equally important hypotheses that could lead to better clinical outcomes in the future.