Oxaliplatin-induced immune-mediated cytopenias: a case report and literature review.

Oxaliplatin is a third-generation platinum antineoplastic agent that commonly causes diarrhea, nausea, vomiting, myelosuppression, and peripheral neuropathy. Less common adverse effects that are increasingly being reported include acute immune-mediated thrombocytopenia, hemolytic anemia, and pancytopenia. Here, we report a patient case of suspected oxaliplatin-induced immune-mediated thrombocytopenia and a thorough literature evaluation of acute oxaliplatin-induced immune-mediated thrombocytopenia, hemolytic anemia, and pancytopenia that has yet to be reported until now. There have been 39 previously published reports of these cytopenic events with a median number of 16 treatment cycles prior to presentation. Patients experiencing unusual signs and symptoms such as chills, rigors, fever, back pain, abdominal pain, ecchymosis, hematemesis, hematuria, dark urine, hematochezia, petechiae, epistaxis, or mental status changes during or shortly after an oxaliplatin infusion should have complete blood counts ordered and evaluated promptly.

Distinct cellular and therapeutic effects of obatoclax in rituximab-sensitive and -resistant lymphomas.

Bcl-2 proteins represent a rheostat that controls cellular viability. Obatoclax, a BH3-mimetic, has been designed to specifically target and counteract anti-apoptotic Bcl-2 proteins. We evaluated the biological effects of obatoclax on the anti-tumour activity of rituximab and chemotherapy agents. Obatoclax induced cell death of rituximab/chemotherapy-sensitive (RSCL), -resistant cell lines (RRCL) and primary tumour-cells derived from patients with B-cell lymphomas (N=39). Obatoclax also enhanced the activity of rituximab and had synergistic activity when combined with chemotherapy agents. The ability of Obatoclax to induce PARP cleavage varied between patient samples and was not observed in some RRCL. Inhibition of caspase activity did not affect obatoclax activity, suggesting the existence of caspase-independent death pathways. Autophagy was detected by LC3 conversion and/or electron microscopy in RRCL and in patient-derived tumour cells. Moreover, obatoclax activity was inhibited by Beclin-1 knockdown. In summary, obatoclax is an active Bcl-2 inhibitor that potentiates the activity of chemotherapy agents and, to a lesser degree, rituximab. Defining the molecular events triggered by obatoclax is necessary to further its clinical development and identify potential biomarkers that are predictive of response.

Peptide concentrations and mRNA expression of IGF-I, IGF-II and IGFBP-3 in breast cancer and their associations with disease characteristics.

PURPOSE: To measure peptide concentrations and mRNA expression of the IGF Family in breast cancer and to examine their associations with the disease features. EXPERIMENTAL DESIGN: Fresh tumor samples were collected from 348 patients who underwent surgery for breast cancer. Tissue levels of mRNA and peptide of IGF-I, IGF-II, and IGFBP-3 were analyzed with real-time RT-PCR and ELISA, respectively. Cox proportional hazards regression model was used to examine the associations of IGF markers with patient survival. RESULTS: Age was inversely associated with IGF-I, IGF-II and IGFBP-3 at both mRNA and peptide levels. Small tumors, early TNM stages, or low grades were associated with high mRNA expression of IGFs and IGFBP-3. Hormone receptors were positively correlated with IGF-I and IGF-II expression. Survival analysis showed that patients with high expression of one of the IGF-I transcripts, IGF-IA, had lower risk of disease recurrence (HR = 0.47, 95%CI: 0.27-0.81) and death (HR = 0.35, 95%CI: 0.18-0.70) compared to those with low expression. High IGFBP-3 expression was also inversely associated with reduced risk of death (HR = 0.47, 95%CI: 0.23-0.95). Similar associations, however, were not observed when tissue levels of IGF-I peptide or IGFBP-3 protein were analyzed. High IGF-II peptide was related to increased risk of relapse (HR = 1.91, 95%CI: 1.12-3.27). CONCLUSION: Our findings of high mRNA expression of IGFs and IGFBP-3 being associated with less aggressive tumors and favorable prognosis were consistent with previous observations, but were not supported by the measurement of tissue levels of IGF-I peptide and IGFBP-3 protein, suggesting that IGF mRNA expression and tissue levels of IGF peptides are regulated by different mechanisms and assessing these molecules in tumor tissue may have different implications.

Contribution of Msh2 and Msh6 subunits to the asymmetric ATPase and DNA mismatch binding activities of Saccharomyces cerevisiae Msh2-Msh6 mismatch repair protein.

Previous analyses of both Thermus aquaticus MutS homodimer and Saccharomyces cerevisiae Msh2-Msh6 heterodimer have revealed that the subunits in these protein complexes bind and hydrolyze ATP asymmetrically, emulating their asymmetric DNA binding properties. In the MutS homodimer, one subunit (S1) binds ATP with high affinity and hydrolyzes it rapidly, while the other subunit (S2) binds ATP with lower affinity and hydrolyzes it at an apparently slower rate. Interaction of MutS with mismatched DNA results in suppression of ATP hydrolysis at S1-but which of these subunits, S1 or S2, makes specific contact with the mismatch (e.g., base stacking by a conserved phenylalanine residue) remains unknown. In order to answer this question and to clarify the links between the DNA binding and ATPase activities of each subunit in the dimer, we made mutations in the ATPase sites of Msh2 and Msh6 and assessed their impact on the activity of the Msh2-Msh6 heterodimer (in Msh2-Msh6, only Msh6 makes base specific contact with the mismatch). The key findings are: (a) Msh6 hydrolyzes ATP rapidly, and thus resembles the S1 subunit of the MutS homodimer, (b) Msh2 hydrolyzes ATP at a slower rate, and thus resembles the S2 subunit of MutS, (c) though itself an apparently weak ATPase, Msh2 has a strong influence on the ATPase activity of Msh6, (d) Msh6 binding to mismatched DNA results in suppression of rapid ATP hydrolysis, revealing a "cis" linkage between its mismatch recognition and ATPase activities, (e) the resultant Msh2-Msh6 complex, with both subunits in the ATP-bound state, exhibits altered interactions with the mismatch.

Secondary pancreatic involvement by a diffuse large B-cell lymphoma presenting as acute pancreatitis.

Diffuse large B-cell lymphoma is the most common type of non-Hodgkin's lymphoma. More than 50% of patients have some site of extra-nodal involvement at diagnosis, including the gastrointestinal tract and bone marrow. However, a diffuse large B-cell lymphoma presenting as acute pancreatitis is rare. A 57-year-old female presented with abdominal pain and matted lymph nodes in her axilla. She was admitted with a diagnosis of acute pancreatitis. Abdominal computed tomography (CT) scan showed diffusely enlarged pancreas due to infiltrative neoplasm and peripancreatic lymphadenopathy. Biopsy of the axillary mass revealed a large B-cell lymphoma. The patient was classified as stage IV, based on the Ann Arbor Classification, and as having a high-risk lymphoma, based on the International Prognostic Index. She was started on chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone). Within a week after chemotherapy, the patient's abdominal pain resolved. Follow-up CT scan of the abdomen revealed a marked decrease in the size of the pancreas and peripancreatic lymphadenopathy. A literature search revealed only seven cases of primary involvement of the pancreas in B-cell lymphoma presenting as acute pancreatitis. However, only one case of secondary pancreatic involvement by B-cell lymphoma presenting as acute pancreatitis has been published. Our case appears to be the second report of such a manifestation. Both cases responded well to chemotherapy.

Quality of life and hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common and rapidly fatal cancer ranking third among the leading causes of cancer-related deaths. Potentially curative therapies like surgery, transplant and ablation are not an option for most patients as they are often diagnosed when the disease is advanced. Liver directed therapy and oral targeted therapies are used in these patients to prolong life and palliate symptoms of the cancer and associated liver failure. Overall survival remains poor and hence health-related quality of life (HRQoL) is of paramount importance in these patients. As novel therapies are developed to improve outcomes, a comprehensive knowledge of available tools to assess impact on QoL is needed. Hence we reviewed all the studies in HCC patients published within the last 13 years from 2001-2013 which assessed HRQoL as a primary or secondary endpoint. A total of 45 studies and 4 meta-analysis were identified. Commonly used tools were European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) (15 studies) and the Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire (FACT-Hep) (14 studies). Of the 45 publications which incorporated HRQoL as end-point only 24 were clinical trials, 17/24 (71%) assessed systemic therapies while 7/24 (29%) assessed liver-directed therapies. Majority of the publications (trials + retrospective reviews) that had HRQoL as an endpoint in HCC patients were studies evaluating liver-directed therapies (23/45 or >50%). We discuss the measures included in the tools, their interpretation, and summarize existing QoL data that will help design future HCC trials.

Dacetuzumab, a humanized mAb against CD40 for the treatment of hematological malignancies.

Dacetuzumab, a humanized mAb targeting the CD40 antigen, is in development by Seattle Genetics Inc and licensee Genentech Inc for the potential treatment of hematological malignancies. The CD40 antigen is a highly expressed cell surface transmembrane protein that is present in normal B-cells. Experiments using blocking antibodies for the CD40 ligand demonstrated that CD40 signaling may play a role in the development and maintenance of B-cell hematological malignancies and some solid tumors. In vitro, dacetuzumab exhibited antitumor activity against several B-cell lymphoma and multiple myeloma (MM) cell lines, and induced direct apoptosis as well as the engagement of effective antibody-dependent cell-mediated cytotoxicity. In vivo, dacetuzumab demonstrated enhanced antitumor efficacy in combination with other mAbs and chemotherapeutic agents; many of these combinations are now being tested clinically. Early clinical trials have evaluated the pharmacokinetics, safety and efficacy of dacetuzumab monotherapy in patients with relapsed/refractory B-cell lymphomas or MM. Targeting CD40 with dacetuzumab resulted in modest antitumor activity in B-cell lymphomas and, to a lesser extent, in MM. In particular, patients with diffuse large B-cell lymphoma responded well to dacetuzumab; the drug is being pursued for this indication in phase II trials.