Considerable evidence has implicated matrix metalloproteinases (MMPs), a group of zinc-dependent endopeptidases, in the degradation of extracellular matrix (ECM) during the metastatic process. Most MMPs are secreted as inactive zymogens and are activated extracellularly. Over expression of MMP-1, -2, -3. -7, -9, -13, and MT1-MMP has been demonstrated in human colorectal cancers. The degree of over expression of some MMPs has been noted to correlate with stage of disease and/or prognosis. An unresolved debate has centered on whether MMPs are produced by the stromal cells surrounding a tumor or by the colorectal cancer cells themselves. MMP-7 is produced abundantly by colorectal cancer cells. The presence of a mutation in the APC gene results in nuclear accumulation of the beta-Catenin/TCF complex, which serves as a transcriptional factor that upregulates MMP-7 expression. Increased expression of MMP-3 in colorectal cancer correlates with low levels of microsatelite instability and poor prognosis. Increased levels of MMP-9 (produced primarily by inflammatory cells) have been demonstrated early in the transition from colon adenoma to adenocarcinoma. In contrast to other MMPs, overexpression of MMP-12 is associated with increased survival in colorectal cancer, presumably as a result of an inhibitory effect on angiogenesis. Based on the assumption that MMPs were responsible for metastasis, several orally active, low molecular weight inhibitors of MMPs (MMPIs) have been developed. These MMPIs have been effective in controlling cancer progression in animals, but have failed to prolong survival in phase III clinical trials in patients with advanced cancer. MMPIs have not yet been evaluated in patients with colorectal cancer.

Patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) are treated with salvage regimens and may be considered for high-dose chemotherapy and autologous stem cell transplantation if disease is chemosensitive. Bendamustine is active in indolent B cell lymphomas and chronic lymphocytic leukemia but has not been extensively studied in aggressive lymphomas. This trial examines the combination of bendamustine and rituximab in patients with relapsed and refractory DLBCL. Patients received bendamustine at 90 mg/m2 (n = 2) or 120 mg/m2 (n = 57) on days 1 and 2 and rituximab at 375 mg/m2 on day 1 every 28 days for up to 6 cycles. The study evaluated objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and treatment safety. Fifty-nine patients were treated, and 48 were evaluable for response. Median age was 74; 89 % had stage III or IV disease, and 63 % had high revised International Prognostic Index scores; the median number of prior therapies was 1. Based on analysis using the intent-to-treat population, the ORR was 45.8 % (complete response, 15.3 %; partial response, 30.5 %). The median DOR was 17.3 months, and the median PFS was 3.6 months. Grade 3 or 4 hematological toxicities included neutropenia (36 %), leukopenia (29 %), thrombocytopenia (22 %), and anemia (12 %). The combination of bendamustine and rituximab showed modest activity in patients with relapsed and refractory DLBCL and has an acceptable toxicity profile.

Background. Esophageal squamous cell carcinomas (ESCCs) and esophageal adenocarcinomas (EACs) account for .95% of esophageal malignancies and represent a major global health burden. ESCC is the dominant histology globally but represents a minority of U.S. cases, with EAC accounting for the majority of U.S. cases.The patient outcomes for advanced ESCC and EAC are poor, and new therapeutic options are needed. Using a sensitive sequencing assay, we compared the genomic profiles of ESCC and EAC with attention to identification of therapeutically relevant genomic alterations. Methods. Next-generation sequencing-based comprehensive genomic profiling was performed on hybridization-captured, adaptor ligation-based libraries to a median coverage depth of .6503 for all coding exons of 315 cancer-related genes plus selected introns from 28 genes frequently rearranged in cancer.Results from a single sample were evaluated for all classes of genomic alterations (GAs) including point mutations, short insertions and deletions, gene amplifications, homozygous deletions, and fusions/rearrangements. Clinically relevant genomic alterations (CRGAs) were defined as alterations linked to approved drugs and those under evaluation in mechanismdriven clinical trials.Results. There were no significant differences by sex for either tumor type, and the median age for all patients was 63 years.

BACKGROUND: PROCEED (), a large registry, evaluated sipuleucel-T immunotherapy for asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). METHODS: PROCEED enrolled mCRPC patients receiving three biweekly sipuleucel-T infusions. Assessments included: overall survival (OS); serious adverse events (SAEs); cerebrovascular events (CVEs); and anticancer interventions (ACIs). Follow-up was ≥3 years, until death, or study withdrawal. RESULTS: 1976 patients (2011–2017) were followed for 46.6 months (median). Median age was 72 years and baseline median prostate-specific antigen was 15.0 ng/ml. 86.7% were Caucasians and 11.6% African American. 1902 patients had ≥1 sipuleucel-T infusion. Median OS was 30.7 (95% confidence interval [CI]: 28.6–32.2) months. Known prognostic factors were independently associated with OS on multivariable analysis. 1255 patients died, 964 (76.8%) from prostate cancer (PC) progression. Median time from first infusion to PC death was 42.7 (95% CI: 39.4–46.2) months. Incidence of sipuleucel-T-related SAEs was 3.9%. Incidence of CVEs was 2.8% and the rate per 100 person-years was 1.2 (95% CI: 0.9–1.6). CVE incidence among 11,972 mCRPC patients from the SEER-Medicare database was 2.8%; 1.5 [95% CI 1.4–1.7]/100 person-years. 77.7% of patients received ≥1 ACI (abiraterone, enzalutamide, docetaxel, cabazitaxel, or radium-223) after sipuleucel-T; 32.5% and 17.4% of patients experienced a 1- and 2-year treatment-free interval, respectively. CONCLUSIONS: PROCEED provides contemporary survival data for sipuleucel-T-treated men in a real-world setting of new life-prolonging agents, which will be useful in discussing treatment options with patients and in powering future trials with sipuleucel-T. Safety and tolerability of sipuleucel-T in PROCEED was consistent with previous findings.