A retrospective analysis of tolerance and outcomes of cutaneous malignant melanoma in patients receiving adjuvant interferon-alpha 2B: a community oncology perspective.

INTRODUCTION: Interferon alpha 2B (IFN-α) therapy in malignant melanoma has improved relapse free survival and overall survival but is considerably toxic and lowers the overall quality of life (QoL) substantially. A significant number of patients do not complete the full duration (one year) of therapy. OBJECTIVE: The aim of this study was to evaluate patients' ability to tolerate IFN-α therapy and to compare our results to reported data in the literature. METHODS: We conducted a retrospective review of patients diagnosed with cutaneous malignant melanoma who received IFN therapy after surgical resection. Patients were divided into two groups: patient who completed therapy (CIT) and those who did not (incomplete therapy, IIT). Duration of therapy was calculated. Reason for discontinuation and experienced side effects were reported. Statistical significance was determined at p < 0.05. RESULTS: A total of 64 patients were included in the review. There were 16 (25%) patients were able to complete therapy. The most common reasons for discontinuing IFN-α therapy was fatigue (81.3%), fever (40.6%), depression (28.1%) and nausea (18.8%). Patients in the CIT group were younger than those in the IIT group (47.4 ± 14.2 vs 57.8 ± 11.9 years, mean ± SD; p = 0.011). There also seemed to be an association that those with the presence of advanced disease may have been more likely to complete therapy (node positive disease at the time of diagnosis, p = 0.07). LIMITATIONS: It is a retrospective study and has to rely on physician notes for the subjective data. For the survival analyses, the median follow-up times for both of the groups were less than 3.5 years. CONCLUSIONS: Younger patients were more likely to complete therapy. There was a trend towards an association between more advanced disease and the completion of therapy. Most common causes of discontinuation of therapy were fatigue, fever, depression, and nausea.

Evidence for Clinical Differentiation and Differentiation Syndrome in Patients With Acute Myeloid Leukemia and IDH1 Mutations Treated With the Targeted Mutant IDH1 Inhibitor, AG-120.

BACKGROUND: Cancer-associated isocitrate dehydrogenase (IDH) mutations block normal cellular differentiation via production of the oncometabolite, R-2-hydroxyglutarate. In patients with acute myeloid leukemia (AML) receiving targeted mutant IDH inhibitor therapy, neutrophil recovery within the setting of clinical differentiation syndrome (DS) has been anecdotally described. PATIENTS AND METHODS: We describe 3 patients who developed clinically apparent DS during monotherapy with the mutant IDH1 inhibitor, AG-120, for relapsed/refractory AML. RESULTS: AG-120-induced differentiation commenced within the first 60 days of treatment, notably in the same time frame as clinical response, strengthening the purported mechanism of targeted mutant IDH inhibitor therapy via successful myeloid maturation. Symptoms of DS were nonspecific and included culture-negative fever, edema, hypotension, malaise, and pleural and/or pericardial effusions, in addition to marked neutrophil-predominant leukocytosis. CONCLUSION: DS can occur during treatment with targeted mutant IDH1 inhibitor therapy. Patients might present with nonspecific clinical manifestations often in the setting of leukocytosis related to exuberant neutrophil recovery. Prompt identification and initiation of treatment interventions, including hydroxyurea, corticosteroids, and/or consideration of temporary treatment discontinuation, are important to facilitate prompt resolution.

Tumor molecular profiling in the treatment of refractory cancers.

INTRODUCTION: Molecular profiling (MP) has been used as a technique to identify treatment regimens for individual patient's cancer. The results of MP has been used to guide targeted therapy specific to each patient's tumor that resulted in a longer progression free survival (PFS) compared to the last conventional treatment. This study aims to provide further data to delineate the PFS of patients who get treated with targeted therapy based on MP. METHODS: A retrospective chart review was performed. The patients were greater than 18 years of age refractory to at least one standard treatment and enrolled in the study: "A Clinical Data Registry Study of Patients with Advanced Refractory Cancers Electing OncInsights as a Method to Support Physician Choice of Drug Therapy". The location is a West Michigan Hematology-Oncology private practice during the period of 07/2010-02/2013. We considered the molecular profiled treatment regimen a success if the PFS ratio was ≥ 1.3. RESULTS: 18 patients were included in the study. 55% were male and 45% were female with median age of 57.67 +/- 12.02 at the time of diagnosis. 4/18 (22%) patients achieved a PFS ratio >1.3. The patients with a PFS ratio ≥ 1.3 included GIST (imatinib- > sunitinib); angiosarcoma (docetaxel- > sorafenib, pravastatin); thymoma (paclitaxel- > desatinib); and angiosarcoma (gemcitabine- > sunitinib). CONCLUSION: This study demonstrates the potential value of molecular profiling in patients refractory to prior chemotherapeutic agents in a community setting. Continued work on rapid implementation of molecular profiling earlier in the care of oncology patients continues to be a future goal.

Spontaneous Regression of Refractory Diffuse Large B-Cell Lymphoma with Improvement in Immune Status with ART in a Patient with HIV: A Case Report and Literature Review.

BACKGROUND: Diffuse large B-cell lymphoma accounts for the large majority of AIDS-related non-Hodgkin lymphoma. Traditionally, this lymphoma has been treated with CHOP-like regimens with the recent addition of rituximab. We report a unique case where an HIV-infected patient with diffuse large B-cell lymphoma had complete regression of the lymphoma with continued antiretroviral therapy (ART) after chemotherapy was stopped. CASE REPORT: A 55-year-old man who presented with fatigue and weight loss had initial CT findings of bilateral renal masses during his workup. Biopsy revealed diffuse large B-cell lymphoma and subsequently he was also diagnosed with HIV. He completed 6 cycles of CHOP-like (4 cycles of EPOCH-R and 2 cycles of R-CHOP) first-line therapy with significant dose delays and dose reductions due to severe adverse effects. Chemotherapy was stopped due to physical deconditioning and intolerable adverse effects. He had a FDG-PET/CT showing progression of his disease 8 weeks after completing chemotherapy. He was maintained only on ART after finishing 6 cycles of chemotherapy. With this therapy alone and with improvement in his immune status, his lymphoma regressed completely. CONCLUSIONS: There are very few reported cases in which lymphoma has regressed with treatment of HIV alone, as is regression of diffuse large B-cell lymphoma. This case emphasizes that ART can lead to immune reconstitution of HIV-infected patients and can establish the anti-tumor effect, causing regression of the lymphoma.

Making the LINC: SUN and KASH protein interactions.

Cell nuclei are physically integrated with the cytoskeleton through the linker of nucleoskeleton and cytoskeleton (LINC) complex, a structure that spans the nuclear envelope to link the nucleoskeleton and cytoskeleton. Outer nuclear membrane KASH domain proteins and inner nuclear membrane SUN domain proteins interact to form the core of the LINC complex. In this review, we provide a comprehensive analysis of the reported protein-protein interactions for KASH and SUN domain proteins. This critical structure, directly connecting the genome with the rest of the cell, contributes to a myriad of cellular functions and, when perturbed, is associated with human disease.

Probing nuclear pore complex architecture with proximity-dependent biotinylation.

Proximity-dependent biotin identification (BioID) is a method for identifying protein associations that occur in vivo. By fusing a promiscuous biotin ligase to a protein of interest expressed in living cells, BioID permits the labeling of proximate proteins during a defined labeling period. In this study we used BioID to study the human nuclear pore complex (NPC), one of the largest macromolecular assemblies in eukaryotes. Anchored within the nuclear envelope, NPCs mediate the nucleocytoplasmic trafficking of numerous cellular components. We applied BioID to constituents of the Nup107-160 complex and the Nup93 complex, two conserved NPC subcomplexes. A strikingly different set of NPC constituents was detected depending on the position of these BioID-fusion proteins within the NPC. By applying BioID to several constituents located throughout the extremely stable Nup107-160 subcomplex, we refined our understanding of this highly conserved subcomplex, in part by demonstrating a direct interaction of Nup43 with Nup85. Furthermore, by using the extremely stable Nup107-160 structure as a molecular ruler, we defined the practical labeling radius of BioID. These studies further our understanding of human NPC organization and demonstrate that BioID is a valuable tool for exploring the constituency and organization of large protein assemblies in living cells.

An unusual case of swelling--Clarkson's syndrome.

Clarkson's syndrome, also called idiopathic systemic capillary leak syndrome is a rare condition characterised by vascular hyper permeability resulting in extreme intravascular volume depletion. The syndrome is unique and almost paradoxical in its presentation, with findings initially suggesting overwhelming heart failure, but in reality the extra vascular fluid represents overt capillary leak, with ultimate intravascular volume depletion, a low output state and hypovolemic shock. Previously described characteristics have classically included severe oedema and anasarca with rapid, profound shock, typically accompanied by haemoconcentration. The authors describe a patient, initially seeming benign in presentation, who rapidly progressed with confusing findings of fluid overload by examination and imaging, ultimately manifesting these findings by severe capillary leak rather than hydrostatic oedema, with ultimate hypovolaemic shock, multisystem organ failure and death. Our aim is that by describing clinical, haemodynamic and pathologic descriptors of the disease, the authors can aid in increasing physician awareness of this unusual syndrome.