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Purpose: Improved therapies and imaging modalities are needed for the treatment of breast cancer brain metastases (BCBM). ANG1005 is a drug conjugate consisting of paclitaxel covalently linked to Angiopep-2, designed to cross the blood-brain barrier. We conducted a biomarker substudy to evaluate 18 F-FLT-PET for response assessment., Methods: Ten patients with measurable BCBM received ANG1005 at a dose of 550 mg/m 2 IV every 21 days. Before and after cycle 1, patients underwent PET imaging with 18 F-FLT, a thymidine analog, retention of which reflects cellular proliferation, for comparison with gadolinium-contrast magnetic resonance imaging (Gd-MRI) in brain metastases detection and response assessment. A 20 % change in uptake after one cycle of ANG1005 was deemed significant., Results: Thirty-two target and twenty non-target metastatic brain lesions were analyzed. The median tumor reduction by MRI after cycle 1 was -17.5 % (n = 10 patients, lower, upper quartiles: -25.5, -4.8 %) in target lesion size compared with baseline. Fifteen of twenty-nine target lesions (52 %) and 12/20 nontarget lesions (60 %) showed a ≥20 % decrease post-therapy in FLT-PET SUV change (odds ratio 0.71, 95 % CI: 0.19, 2.61). The median percentage change in SUV max was -20.9 % (n = 29 lesions; lower, upper quartiles: -42.4, 2.0 %), and the median percentage change in SUV 80 was also -20.9 % (n = 29; lower, upper quartiles: -49.0, 0.0 %). Two patients had confirmed partial responses by PET and MRI lasting 6 and 18 cycles, respectively. Seven patients had stable disease, receiving a median of six cycles., Conclusions: ANG1005 warrants further study in BCBM. Results demonstrated a moderately strong association between MRI and 18 F-FLT-PET imaging.

Introduction: Diffuse large B-cell lymphoma (DLBCL) is a molecularly heterogeneous disease defined by different cellular origins and mechanisms of oncogenic activation. Approximately 10% of DLBCL cases harbor a MYC rearrangement and this has been associated with a more aggressive clinical course following standard therapy., Areas Covered: So-called 'double-hit lymphomas' (DHL) or 'triple hit lymphomas' (THL) occur when MYC is concurrently rearranged with BCL2 and/or BCL6. These tumors are characterized by high proliferation rate and a very poor outcome following standard R-CHOP (rituximab, cyclophosphamide, doxorubicin vincristine and prednisone) therapy, in most (though not all) studies that have looked at this. Though there is a paucity of published experience with other chemotherapy regimens, there is emerging evidence that more intensive approaches may improve outcome. Recently, there has been a lot of focus in the literature on 'double-expresser lymphomas' (DEL) with high MYC, BCL2 and/or BCL6 expression but typically without rearrangements of these genes. These DEL cases, have a poor outcome with R-CHOP and there is little consensus on how they should be approached. Expert commentary: This review will focus on the biology and treatment of DHL and DEL, discuss the outcome of these diseases with current standard as well as promising new approaches and conclude with a section on novel agents that are in development for these diseases.

Importance: The strength of association between surrogate end points and survival in oncology is important to understand because surrogate end points are frequently used in oncology clinical trials, supporting US Food and Drug Administration approvals and National Comprehensive Cancer Network guideline recommendations., Objective: To identify and evaluate trial-level meta-analyses of randomized clinical trials quantifying the association between a surrogate end point and overall survival in medical oncology. Trial-level correlations test whether treatments that improve the surrogate end point also improve the final end point and are widely considered the strongest evidence to validate a surrogate end point., Evidence Review: Our literature search was built on earlier reported data sets and updated with Google Scholar and MEDLINE searches conducted on December 26, 2014. For MEDLINE, search terms included ("regression" or "correlation") and "surrogate" and "end point [or endpoint]" and ("oncology" or "cancer"). For Google scholar, search terms included ("regression" or "correlation") and "surrogate end point [or endpoint]" and "overall survival" and "trial level." A total of 108 abstracts were retrieved, and 62 articles were read in full in addition to articles identified through prior reviews., Findings: We found 36 articles in which 65 specific correlations between a surrogate end point and survival were identified. Surrogate end points were studied in the neoadjuvant, adjuvant, locally advanced, and metastatic settings. The most common sources for trials included in the 36 articles were systematic reviews of the published literature (10 of 36; 28%), and published literature and meeting abstracts (14 of 36; 39%). Four meta-analyses (11%) used a convenience sample, and only 5 studies (14%) attempted to include unpublished trials by surveying clinical trial registries. Among these 5 studies, only 352 of 684 eligible trials (51.1%) were included in the analyses. More than half of reported correlations (34 of 65; 52%) were of low strength (r ≤ 0.7). Approximately a quarter (16 of 65; 25%) were of medium strength (r > 0.7 to r < 0.85), and 15 of 65 (23%) were highly correlated (r ≥ 0.85) with survival., Conclusions and Relevance: Most trial-level validation studies of surrogate end points in oncology find low correlations with survival. All validation studies use only a subset of available trials. The evidence supporting the use of surrogate end points in oncology is limited.

Lessons Learned: Accrual to cervical cancer studies remains a puzzling challenge given the lack of options and the dismal prognosis of this disease. The majority of patients referred for a trial such as this have very advanced disease that is difficult to manage.The observation of 4 partial responses among the 41 patients indicates that ixabepilone has some activity but not sufficient for further development without greater understanding of mechanisms of sensitivity and resistance., Background: Ixabepilone is a microtubule-stabilizing agent approved for metastatic breast cancer. Preclinical data have shown that ixabepilone is active in taxane-sensitive and -resistant cells. Metastatic cervical carcinoma (mCC) has a poor prognosis and no established second-line therapies. This study assessed the efficacy and safety of ixabepilone in previously treated mCC., Methods: Patients with histologically confirmed mCC and at least one prior cisplatin-containing regimen were treated with ixabepilone [6 mg/m(2) per day for 5 days] every 21 days. The primary endpoint was progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were response rate, rate of tumor growth, overall survival (OS), and safety. Levels of glu-terminated and acetylated tubulin, markers of microtubule stabilization, and surrogates for target engagement were assessed by Western blot., Results: In total, 41 patients were enrolled; 34 had tumors with primarily squamous histology. The median number of prior therapies was 2 (range 1-6). Four patients (9.7%) had a partial response. Median PFS in months was 2.3 for all, 3.84 for taxane-naïve, and 2.03 for taxane-pretreated patients (p = .13). Consistent with this, we found statistically similar (p = 1) rates of growth in taxane-naive patients (0.0035 per day) and taxane pretreated patients (0.0053 per day). Median OS was 5.84 months. G1/2 toxicities included vomiting (43%), sensory neuropathy (21%), and fatigue (60%). Bowel fistulas were observed in 7% of patients. Glu and acetylated tubulin were assessed in tumor samples from 11 patients during the first cycle of treatment. Although there was clear evidence of "target engagement" and microtubule stabilization in all tumors, a correlation between the extent of tubulin stabilization and response to therapy could not be demonstrated., Conclusion: Ixabepilone was well tolerated but showed very modest activity in second- or later-line mCC and cannot be recommended as a therapy. Target engagement was demonstrated but was not correlated with responses, suggesting that other factors mediate drug sensitivity. New strategies are needed for refractory mCC., (©AlphaMed Press; the data published online to support this summary is the property of the authors.)

Background: Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have been evaluated in patients with metastatic and advanced non-small cell lung cancer (NSCLC). The U.S. Food and Drug Administration initially granted accelerated approval to gefitinib but subsequently rescinded the authorization. Erlotinib and afatinib are similar compounds approved for the treatment of metastatic NSCLC. The objective of this study was to compare the efficacy and toxicity of erlotinib, gefitinib, and afatinib in NSCLC., Methods: We tabulated efficacy variables including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) and quantitated toxicities and rates of dose reductions and discontinuation. Summary odds ratios were calculated using random and fixed-effects models. An odds ratio was the summary measure used for pooling of studies., Results: We examined 28 studies including three randomized trials with afatinib. Clinical toxicities, including pruritus, rash, anorexia, diarrhea, nausea, fatigue, mucositis, paronychia, and anemia, were similar between erlotinib and gefitinib, although some statistical differences were observed. Afatinib treatment resulted in more diarrhea, rash, and paronychia compared with erlotinib and gefitinib. Regarding efficacy, similar outcomes were recorded for ORR, PFS, or OS in the total population and in specific subgroups of patients between erlotinib and gefitinib. All three TKIs demonstrated higher ORRs in first line in tumors harboring EGFR mutations., Conclusion: Gefitinib has similar activity and toxicity compared with erlotinib and offers a valuable alternative to patients with NSCLC. Afatinib has similar efficacy compared with erlotinib and gefitinib in first-line treatment of tumors harboring EGFR mutations but may be associated with more toxicity, although further studies are needed. Gefitinib deserves consideration for U.S. marketing as a primary treatment for EGFR-mutant NSCLC., (©AlphaMed Press.)

The paradigm that microtubule-targeting agents (MTAs) cause cell death via mitotic arrest applies to rapidly dividing cells but cannot explain MTA activity in slowly growing human cancers. Many preferred cancer regimens combine a MTA with a DNA-damaging agent (DDA). We hypothesized that MTAs synergize with DDAs by interfering with trafficking of DNA repair proteins on interphase microtubules. We investigated nine proteins involved in DNA repair: ATM, ATR, DNA-PK, Rad50, Mre11, p95/NBS1, p53, 53BP1, and p63. The proteins were sequestered in the cytoplasm by vincristine and paclitaxel but not by an aurora kinase inhibitor, colocalized with tubulin by confocal microscopy and coimmunoprecipitated with the microtubule motor dynein. Furthermore, adding MTAs to radiation, doxorubicin, or etoposide led to more sustained γ-H2AX levels. We conclude DNA damage-repair proteins traffic on microtubules and addition of MTAs sequesters them in the cytoplasm, explaining why MTA/DDA combinations are common anticancer regimens.

Introduction: Adrenocortical carcinoma (ACC) is a heterogeneous and rare disease. At presentation or at the time of a recurrence, the disease commonly spreads to the liver, lungs, lymph nodes, and bones. The brain has only rarely been reported as a site of metastases., Objective: The aims of this report were to describe the clinical characteristics of patients with ACC who developed brain metastasis and were evaluated at the National Cancer Institute., Methods: We describe the history and clinical presentation of six patients with ACC and metastatic disease in the brain. Images of the six patients and pathology slides were reviewed when available., Results: The median age at the time of the diagnosis of ACC was 42 years. The median time from the initial diagnosis until the presentation of brain metastasis was 43 months. As a group the patients had previously received multiples lines of chemotherapy (median of three), and they presented with one to three metastatic brain lesions. Four patients underwent metastasectomy, one had radiosurgery, and one had both modalities. Two patients are still alive, three died, between 2 and 14 months after the diagnosis of brain metastases, and one was lost to follow-up., Conclusion: Patients with advanced ACC can rarely present with metastasis to the brain, most often long after the initial diagnosis. Timely diagnosis of brain metastasis with appropriate intervention after discussion in a multidisciplinary meeting can improve the prognosis in this particular scenario.

Introduction: The past decade has seen the development and widespread use of tyrosine kinase inhibitors (TKIs) targeting a mutated EGFR (mEGFR) for the treatment of metastatic NSCLC. We discuss the main properties of the TKIs currently recommended for the treatment of mEGFR NSCLC: gefitinib, erlotinib and afatinib., Areas Covered: The mechanism of action, pharmacodynamics and pharmacokinetics of these drugs, with emphasis on the historical context of their preclinical and clinical development, will be covered, including potential resistance mechanisms to these first-generation TKIs that has driven the trial design for second and third generations of EGFR inhibitors. Six Phase III clinical trials comparing these three TKIs with cisplatin-based chemotherapy upfront for mEGFR NSCLC provide the basis for the comparative safety and toxicity analysis between these agents. Class-related toxicity of these EGFR inhibitors, including life-threatening effects, will be discussed., Expert Opinion: Toxicity and safety analysis from the Phase III trials of these agents in mEGFR populations suggests that afatinib has more frequent and severe side effects. Given that an efficacy advantage has not yet been demonstrated for afatinib over erlotinib and gefitinib, the consistent class toxicity profile of these agents means that gefitinib and erlotinib are a safer first-line treatment recommendation.

Cancer treatment is being revolutionized by the emergence of immunotherapies such as immune checkpoint inhibitors and therapeutic cancer vaccines. Prostate cancer is amenable to such therapeutic approaches. The improved understanding of the relationship between the immune system and tumors has allowed therapeutic targeting of immune checkpoints and tumor associated antigens to be developed. Furthermore, interventions used in prostate cancer are capable of impacting the immune system. As demonstrated by preclinical data and emerging clinical data, radiation therapy, anti-androgen therapy, and chemotherapy can be used with immunotherapies to obtain synergistic results. Current and future clinical trials will further investigate these principles as immunotherapeutics are combined with each other and standard therapies for optimal clinical utility.

The mitogen-activated protein kinase/extracellular signal-regulated (MAPK/ERK) pathway is activated by upstream genomic events and/or activation of multiple signaling events in which information coalesces at this important nodal pathway point. This pathway is tightly regulated under normal conditions by phosphatases and bidirectional communication with other pathways, like the protein kinase B/mammalian target of rapamycin (AKT/m-TOR) pathway. Recent evidence indicates that the MAPK/ERK signaling node can function as a tumor suppressor as well as the more common pro-oncogenic signal. The effect that predominates depends on the intensity of the signal and the context or tissue in which the signal is aberrantly activated. Genomic profiling of tumors has revealed common mutations in MAPK/ERK pathway components, such as v-raf murine sarcoma viral oncogene homolog B1 (BRAF). Currently approved for the treatment of melanoma, inhibitors of BRAF kinase are being studied alone and in combination with inhibitors of the MAPK and other pathways to optimize the treatment of many tumor types. Therapies targeted toward MAPK/ERK components have various response rates when used in different solid tumors, such as colorectal cancer and ovarian cancer. Understanding the differential nature of activation of the MAPK/ERK pathway in each tumor type is critical in developing single and combination regimens, because different tumors have unique mechanisms of primary and secondary signaling and subsequent sensitivity to drugs., (© 2014 American Cancer Society.)

Advances in molecular biology and bioinformatics have resulted in the identification of a number of potential biomarkers that could be relevant in the management of patients with non-small-cell lung cancer (NSCLC). Although there is an increasing amount of literature related to these biomarkers, major issues need to be resolved including validity and reproducibility of results. Additionally, in order to interpret the existing literature accurately, a clear distinction must be made between the prognostic and predictive value of biomarkers. The practical applicability of biomarker discovery for patients with lung cancer includes the identification of patients with early-stage NSCLC who are most likely to benefit from adjuvant therapy. Information gleaned from biomarkers has the potential to help in evaluating the role of targeted therapies including immunotherapy in the neoadjuvant and adjuvant setting. The role of gene signatures and the use of newer platforms such as RNA, methylation, and protein signatures is being explored in patients with early-stage NSCLC. This review focuses on the applications of biomarker discovery in patients with early-stage NSCLC.

Head and neck cancer is a major source of morbidity and mortality worldwide. Intervention during the early phases of carcinogenesis represents a promising new strategy for curbing the devastating effects of this disease and its primary treatment modalities, surgery and radiation with or without concomitant chemotherapy. This review focuses on the peroxisome proliferator-activated receptor gamma (PPARγ) as a target for chemoprevention of oral cancer. Accumulating data suggest that ligands of PPARγ, which include the thiazolidinedione class of agents approved for the treatment of diabetes, inhibit cancer cell growth in vitro and in animal carcinogenesis models, providing the rationale for testing this approach in populations at risk for head and neck cancer., (Published by Elsevier Ltd.)

Introduction: Monoclonal antibodies and small molecules targeting the VEGF pathway are part of the arsenal to treat malignant tumors. Antiangiogenesis therapies has been studied in breast cancer with partial success, reflected by the approval of bevacizumab in Europe but not in United States, for metastatic breast cancer (mBC). Ramucirumab is a mAb against VEGFR-2 interfering with the normal activation of this receptor by its natural ligand VEGF., Areas Covered: This article will review the preclinical data available to date for ramucirumab, as well as survey the main clinical trials of antiangiogenic agents reported in breast cancer, focusing on Phase III clinical trials. It will also review the clinical trial data for ramucirumab in mBC, including the design of the Phase II trials, and report on the preliminary results of the TRIO-012 trial. This trial did not meet its primary end point in progression-free survival and has to be considered as a negative trial., Expert Opinion: Despite preliminary positive data with ramucirumab in other metastatic solid tumors reported to date, the results of TRIO-012 discourage pursuing more efforts with ramucirumab in mBC unless predictive and reproducible biomarkers can be established to select those patients who are most likely to benefit from it.

Background: The US FDA and the EMA have approved seven agents for the treatment of renal cell carcinoma, primarily based on differences in progression-free survival (PFS). Because PFS is an arbitrary endpoint we hypothesized that an analysis would demonstrate the growth rate of tumors remained constant at the time of RECIST-defined disease progression., Methods: We previously estimated the growth (g) and regression (d) rates and the stability of g using data from the Phase III trial comparing sunitinib and interferon., Results: Sufficient data were available and rate constants statistically valid in 321 of 374 patients randomized to sunitinib. Median d was 0•0052 days(-1); in 53 patients no tumor growth was recorded. Median g was 0•00082 days(-1) and was stable for a median of 275 days on therapy, remaining stable beyond 300, 600 and 900 days in 122, 65 and 27 patients, respectively. A possible increase in g while receiving sunitinib could be discerned in only 18 of 321 patients. Given a median g of 0•00082 days(-1) the estimated median time to a second progression were sunitinib continued past RECIST-defined progression was 7.3 months. At 100, 200, and 300 days after starting therapy, an estimated 47%, 27%, and 13% of tumor remains sunitinib sensitive and could explain a RECIST-defined response to a new TKI., Conclusion: Prolonged stability of g with sunitinib suggests continued sunitinib beyond RECIST-defined progression may provide a beneficial outcome. Randomized trials in patients whose disease has "progressed" on sunitinib are needed to test this hypothesis.

We are reporting on a colorectal cancer patient with the longest disease-free interval ever published, where chromosomal microarray analysis was used to confirm the link between the primary and metastatic lesions. This rare case reports on a patient with late recurrence of colorectal cancer in the lung 19 years after its initial diagnosis. We used high-resolution array CGH (aCGH) to analyze the genetic aberrations of both the primary rectal and the recurrent metastatic lung lesions. Interestingly, we found striking similarities between the two lesions, despite the 19 years disease-free interval. In addition, most of the genes that were previously reported to be associated with a high recurrence score showed copy number gains by aCGH in one or both lesions. Our findings suggest that aCGH may be a helpful tool in analyzing the origin of metastases and underline the need for a better understanding of the characteristics of rectal tumors that have a late recurrence potential.

Purpose: To determine tolerability and for the first time explore efficacy of bendamustine-rituximab (BR) in multiply relapsed/refractory hairy cell leukemia (HCL), using two different dose levels of bendamustine., Experimental Design: Patients with HCL with ≥2 prior therapies requiring treatment received rituximab 375 mg/m(2) days 1 and 15 plus bendamustine 70 (n = 6) or 90 (n = 6) mg/m(2), days 1 and 2, for six cycles at 4-week intervals., Results: At 70 and 90 mg/m(2)/dose of bendamustine, overall response rate was 100%, with three (50%) and four (67%) complete remissions (CR) in each respective group. Minimal residual disease (MRD) was absent in 67% and 100% of CRs, respectively. All six without MRD remain in CR at 30 to 35 (median, 31) months of follow-up. Soluble CD22 and CD25 levels decreased with all responses, with median values decreasing from 17.7 and 42 ng/mL at baseline to undetectable and 2 ng/mL after CR, respectively (P < 0.001). Of 12 patients receiving 72 cycles of BR, the most common toxicities were hematologic, including thrombocytopenia (83%), lymphopenia (75%), leukopenia (58%), and neutropenia (42%). Grade III and IV hematologic toxicity included lymphopenia and thrombocytopenia (each 75%), leukopenia (58%), and neutropenia (25%). No significant dose-related differences were detected in response or toxicity., Conclusion: BR has significant activity in HCL. Bendamustine at either 70 or 90 mg/m(2)/dose was highly effective in multiply relapsed/refractory HCL and could be considered for achieving durable CRs without MRD in patients after failure of standard therapies. As it was not dose-limiting, 90 mg/m(2)/dose was chosen for future testing., (©2013 AACR.)

Great strides have been made in improving the outcome of patients with metastatic colorectal cancer and targeted agents are an important part of the treatment arsenal. The approved monoclonal antibodies, bevacizumab, cetuximab and panitumumab, are part of the standard of care, yet only recently have we begun to define which patients benefit from these therapies using predictive tumor biomarkers. More recently, novel agents including aflibercept and regorafenib have had promising results and may become approved therapies. In addition, agents targeting the mTOR pathway and the TNF pathway have demonstrated early evidence of benefit. In the coming years, we may experience an influx of new therapies, possibly leading to further prolongation of patient survival or even, for some, a cure.

Background: Reduced serum levels of adiponectin have been associated with insulin resistance and non-alcoholic fatty liver disease (NAFLD). However, the relationship between serum adiponectin levels and hepatic histology in NAFLD is controversial. The aim of this study was to explore associations between plasma adiponectin concentrations and liver histology in morbidly obese patients., Methods: We conducted a case-control study including obese patients undergoing bariatric surgery and normal controls. Anthropometric, standard biochemical variables as well as plasma adiponectin and leptin levels were determined. Liver biopsy was performed in all patients at the time of surgery., Results: Seventy morbidly obese patients (mean BMI, 40.6 ± 5.6 kg/m(2)) met the inclusion criteria and were compared with 69 controls (mean BMI, 22.8 ± 1.6 kg/m(2), p = 0.0001). Thirty patients (43%) had NAFLD and 20 (28%) of them fulfilled the histological criteria for steatohepatitis. Obesity was associated with increased leptin and decreased adiponectin levels. NAFLD patients exhibited decreased levels of serum adiponectin compared with matched controls [median (Q1-Q3), 3.9 (3.2-4.3) vs. 8.6 (6.5-9.2) μg/mL, p < 0.0001]. In univariate analysis, age, gender, type 2 diabetes mellitus, BMI, HOMA-IR, aspartate aminotransferase (AST), alanine aminotransferase, serum glucose, and adiponectin levels were independently associated with hepatic fibrosis. In multivariate analysis, AST [OR = 1.082 (1.000-1.170)], age [OR = 1.119 (1.023-1.225)], and serum adiponectin levels [OR = 0.529 (0.299-0.936)] were significantly associated with the presence of liver fibrosis., Conclusions: NAFLD patients have lower plasma adiponectin concentrations than control subjects. Low adiponectin levels are associated with more severe liver histology. Serum adiponectin may be useful to estimate the severity of liver damage in obese patients with NAFLD.

Background: Few reports have addressed the value of unfractionated heparin (UFH) or low-molecular-weight heparin in treating the fill spectrum of patients with venous thromboembolism (VTE), including recurrent VTE and pulmonary embolism., Methods: In an open, multicenter clinical trial, 720 consecutive patients with acute symptomatic VTE, including 119 noncritically ill patients (16.5%) with pulmonary embolism and 102 (14.2%) with recurrent VTE, were randomly assigned to treatment with subcutaneous UFH with dose adjusted by activated partial thromboplastin time by means of a weight-based algorithm (preceded by an intravenous loading dose), or fixed-dose (adjusted only to body weight) subcutaneous nadroparin calcium. Oral anticoagulant therapy was started concomitantly and continued for at least 3 months. We recorded the incidence of major bleeding during the initial heparin treatment and that of recurrent VTE and death during 3 months of follow-up., Results: Fifteen (4.2%) of the 360 patients assigned to UFH had recurrent thromboembolic events, as compared with 14 (3.9%) of the 360 patients assigned to nadroparin (absolute difference between rates, 0.3%; 95% confidence interval, -2.5% to 3.1%). Four patients assigned to UFH (1.1%) and 3 patients assigned to nadroparin (0.8%) had episodes of major bleeding (absolute difference between rates, 0.3%; 95% confidence interval, -1.2% to 1.7%). Overall mortality was 3.3% in each group., Conclusions: Subcutaneous UFH with dose adjusted by activated partial thromboplastin time by means of a weight-based algorithm is as effective and safe as fixed-dose nadroparin for the initial treatment of patients with VTE, including those with pulmonary embolism and recurrent VTE.