Phase 1b study of otlertuzumab (TRU-016), an anti-CD37 monospecific ADAPTIR™ therapeutic protein, in combination with rituximab and bendamustine in relapsed indolent lymphoma patients.

PURPOSE: CD37 is cell surface tetraspanin present on normal and malignant B cells. Otlertuzumab (TRU-016) is a novel humanized anti-CD37 protein therapeutic that triggers direct caspase independent apoptosis of malignant B cells and induces antibody-dependent cell-mediated cytotoxicity. This study evaluated the safety, pharmacokinetics, and efficacy of otlertuzumab administered in combination with rituximab and bendamustine to patients with relapsed, indolent B-cell non-Hodgkin Lymphoma (NHL). METHODS: Patients with relapsed or refractory NHL received otlertuzumab (10 or 20 mg/kg) intravenously (IV) on days 1 and 15, bendamustine (90 mg/m(2)) on days 1 and 2, and rituximab (375 mg/m(2)) on day 1 for up to six 28 day cycles. Responses were determined using standard criteria. RESULTS: Twelve patients were treated with 6 patients at each dose level; median age was 57 years (range, 51-79), and median number of prior regimens was 3 (range, 1-4). All patients had relapsed after prior rituximab including 7 refractory to their most recent previous treatment. In the 10 and 20 mg/kg dose cohorts, the mean half-life was 8 and 10 days following the first dose, and 12 or 14 days following 12 doses of otlertuzumab, respectively. Overall response rate was 83% (10/12) with 4 CRs (32%). The most frequent adverse events were neutropenia, nausea, fatigue, leukopenia, and insomnia; most were grade 1 or 2. CONCLUSIONS: Otlertuzumab in combination with rituximab and bendamustine was well tolerated and induced responses in the majority of patients with relapsed indolent B-NHL. NCI Clinical Trials Network registration: NCT01317901.

Non-Hodgkin's lymphomas, version 2.2014.

Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Follicular lymphoma (FL) is the most common subtype of indolent NHL, accounting for approximately 22% of all newly diagnosed cases of NHL. The incorporation of rituximab to chemotherapy regimens has become a widely accepted standard of care for first-line therapy for patients with FL. Maintenance and consolidation therapy with rituximab and radioimmunotherapy have also been associated with improved progression-free survival in patients experiencing response to first-line therapy. Despite therapeutic advances that have improved outcomes, FL is generally considered a chronic disease characterized by multiple recurrences with current therapies. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with FL.

Non-Hodgkin's lymphomas, version 1.2013.

These NCCN Guidelines Insights summarize several key updates to the NCCN Guidelines for Non-Hodgkin's Lymphomas (NHL) and provide a discussion of the clinical evidence that support the updates. The updates discussed in this article feature recommendations for additional treatment options in patients with chronic lymphocytic leukemia and guidance surrounding the management of hepatitis virus reactivation/infections in high-risk patients with NHL undergoing antitumor therapy.

Non-Hodgkin's Lymphomas, version 3.2012.

These NCCN Guidelines Insights summarize several key updates to the 2012 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Hodgkin's Lymphomas (NHL) and describe the clinical evidence supporting the updates. The featured updates include changes to the recommendations for treatment options in patients with chronic lymphocytic leukemia (including in elderly or frail patients and patients with poor-risk cytogenetics), guidance surrounding surveillance imaging for follow-up of patients with NHL, and the addition of first-line consolidation options for patients with mantle cell lymphoma.

Acute lymphoblastic leukemia.

The inaugural NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) were developed as a result of meetings convened by a multi-disciplinary panel of experts in 2011. These NCCN Guidelines provide recommendations on the diagnostic evaluation and workup for ALL, risk assessment, risk-stratified treatment approaches based on the Philadelphia chromosome status and age (adults vs. adolescents/young adults), assessment of minimal residual disease, and supportive care considerations. It is recommended that patients be treated at specialized centers with expertise in the management of ALL.

Tgf-beta signaling alterations and colon cancer.

Colorectal cancer is the second most common cause of cancer-related death in the United States. Twin studies suggest that 35% of all colorectal cancer cases are inherited. High-penetrance tumor susceptibility genes account for at most 3-6% of all colorectal cancer cases and the remainder of the unexplained risk is likely due to a combination of low to moderate penetrance genes. Recent genome-wide association studies have identified several SNPs near genes belonging to the transforming growth factor beta (TGF-beta) superfamily such as GREM1 and SMAD7. Together with the recent discovery that constitutively decreased TGFBR1 expression is a potent modifier of colorectal cancer risk, these findings strongly suggest that germline variants of the TGF-beta superfamily may account for a sizeable proportion of colorectal cancer cases. The TGF-beta superfamily signaling pathways mediate many different biological processes during embryonic development, and in adult organisms they play a role in tissue homeostasis. TGF-beta has a central role in inhibiting cell proliferation and also modulates processes such as cell invasion, immune regulation, and microenvironment modification. Mutations in the TGF-beta type II receptor (TGFBR2) are estimated to occur in approximately 30% of colorectal carcinomas. Mutations in SMAD4 and BMPR1A are found in patients with familial juvenile polyposis, an autosomal dominant condition associated with an increased risk of colorectal cancer. This chapter provides an overview of the genetic basis of colorectal cancer and discusses recent discoveries related to alterations in the TGF-beta pathways and their role in the development of colorectal cancer.

Paclitaxel-Induced Palmar-Plantar Erythrodysesthesia.

Palmar-plantar erythrodysesthesia (PPE) is an uncommon adverse event with paclitaxel. We report a case of PPE due to paclitaxel to create awareness and review management strategies. A 61-year-old female with locally advanced lobular breast cancer was started on neoadjuvant chemotherapy with four cycles of dose-dense doxorubicin and cyclophosphamide. She completed these chemotherapy cycles uneventfully and was started on weekly paclitaxel (80mg/m2) with a gap of two weeks. After receiving the sixth dose of paclitaxel, the patient presented with erythema, swelling, and discomfort of her hands and feet, interfering with her quality of life due to difficulty in carrying out daily routine activities. The changes were acute, occurred within a few days after the sixth dose of paclitaxel, and were consistent with PPE grade 2. Paclitaxel was discontinued, and the patient was switched to docetaxel every three weeks for two cycles. She used emollients and moisturizing creams for her local symptoms, after stopping paclitaxel, erythema, swelling, and discomfort of her hands and feet resolved within two weeks. She did not have a recurrence of these symptoms with docetaxel. Paclitaxel can cause PPE. Its incidence in the literature might be underreported. Discontinuation of paclitaxel can reverse skin toxicity and improve patient's quality of life.

Zinc-induced copper deficiency, sideroblastic anemia, and neutropenia: A perplexing facet of zinc excess.

Hypocupremia due to zinc products can cause sideroblastic anemia and neutropenia and mimics other serious hematological disorders. Early consideration of the copper deficiency and a thorough clinical history can prevent unnecessary interventions.

Strategies to enhance patient adherence: making it simple.

The problem of poor patient adherence has been extensively researched, but the rates of nonadherence have not changed much in the past 3 decades. Healthcare providers play a unique and important role in assisting patients' healthy behavior changes. We conducted a narrative review of the current literature to help providers become more familiar with proven interventions that can enhance patient adherence. We then grouped the interventions into categories that can be remembered by the mnemonic "SIMPLE":1. Simplifying regimen characteristics; 2. Imparting knowledge; 3. Modifying patient beliefs; 4. Leaving the bias; and 6. Evaluating adherence. Chronic lifestyle behavior change often requires a combination of all the aforementioned strategies. We suggest a conceptual framework, which calls for a multidisciplinary approach with the above strategies in the context of a healthcare team and system-related factors. We hope that this framework would not only help design scientifically proven interventions, but also reduce the time and cost involved with implementing these strategies in a healthcare setting.

14-3-3Tau regulates ubiquitin-independent proteasomal degradation of p21, a novel mechanism of p21 downregulation in breast cancer.

14-3-3 proteins regulate many cellular functions, including proliferation. However, the detailed mechanisms by which they control the cell cycle remain to be fully elucidated. We report that one of the 14-3-3 isoforms, 14-3-3tau, is required for the G(1)/S transition through its role in ubiquitin-independent proteasomal degradation of p21. 14-3-3tau binds to p21, MDM2, and the C8 subunit of the 20S proteasome in G(1) phase and facilitates proteasomal targeting of p21. This function of 14-3-3tau may be deregulated in cancer. The overexpression of 14-3-3tau is frequently found in primary human breast cancer and correlates with lower levels of p21 and shorter patient survival. Tenascin-C, an extracellular matrix protein involved in tumor initiation and progression and a known 14-3-3tau inducer, decreases p21 and abrogates adriamycin-induced G(1)/S arrest. It has been known that p21 is required for a proper tamoxifen response in breast cancer. We show that the overexpression of 14-3-3tau inhibits tamoxifen-induced p21 induction and growth arrest in MCF7 cells. Together, the findings of our studies strongly suggest a novel oncogenic role of 14-3-3tau by downregulating p21 in breast cancer. Therefore, 14-3-3tau may be a potential therapeutic target in breast cancer.

Constitutively decreased TGFBR1 allelic expression is a common finding in colorectal cancer and is associated with three TGFBR1 SNPs.

PURPOSE: Constitutively decreased TGFBR1 allelic expression is emerging as a potent modifier of colorectal cancer risk in mice and humans. This phenotype was first observed in mice, then in lymphoblastoid cell lines from patients with microsatellite stable colorectal tumors. PATIENTS AND METHODS: We assessed the frequency of constitutively decreased TGFBR1 allelic expression and association with SNPs covering the TGFBR1 locus using RNA and DNA extracted from the peripheral blood lymphocytes of 118 consecutive patients with biopsy-proven adenocarcinoma of the colon or the rectum. RESULTS: We found that 11(9.3%) of 118 patients exhibited decreased TGFBR1 allelic expression (TGFBR1 ASE). TGFBR1 ASE was strongly associated with three SNPs in linkage disequilibrium with each other: rs7034462 (p = 7.2 x 10-4), TGFBR1*6A (p = 1.6 x 10-4) and rs11568785 (p = 1.4 x 10-4). CONCLUSION: These results confirm the high prevalence of constitutively decreased TGFBR1 allelic expression among patients with colorectal cancer. The association of this phenotype with TGFBR1*6A, rs7034462 and rs1156875 suggests an association between TGFBR1 SNPs and colorectal cancer, which warrants additional studies.

Regulation of p53 by TopBP1: a potential mechanism for p53 inactivation in cancer.

Proper control of the G(1)/S checkpoint is essential for normal proliferation. The activity of p53 must be kept at a very low level under unstressed conditions to allow growth. Here we provide evidence supporting a crucial role for TopBP1 in actively repressing p53. Depletion of TopBP1 upregulates p53 target genes involved in cell cycle arrest and apoptosis and enhances DNA damage-induced apoptosis. The regulation is mediated by an interaction between the seventh and eighth BRCT domains of TopBP1 and the DNA-binding domain of p53, leading to inhibition of p53 promoter binding activity. Importantly, TopBP1 overexpression is found in 46 of 79 primary breast cancer tissues and is associated with high tumor grade and shorter patient survival time. Overexpression of TopBP1 to a level comparable to that seen in breast tumors leads to inhibition of p53 target gene expression and DNA damage-induced apoptosis and G(1) arrest. Thus, a physiological level of TopBP1 is essential for normal G(1)/S transition, but a pathological level of TopBP1 in cancer may perturb p53 function and contribute to an aggressive tumor behavior.