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BackgroundHistone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase inhibitors by increasing their access and binding to DNA.MethodsThis phase I trial was designed to determine the toxicity profile, tolerability, and recommended phase II dose of escalating doses of the HDACi vorinostat, with weekly doxorubicin.ResultsIn total, 32 patients were treated; vorinostat was dosed at 400, 600, 800, or 1000 mg day(-1) on days 1-3, followed by doxorubicin (20 mg m(-2)) on day 3 for 3 of 4 weeks. Maximal tolerated dose was determined to be 800 mg day(-1) of vorinostat. Dose-limiting toxicities were grade 3 nausea/vomiting (two out of six) and fatigue (one out of six) at 1000 mg day(-1). Non-dose-limiting grade 3/4 toxicities included haematological toxicity and venous thromboembolism. Antitumor activity in 24 evaluable patients included two partial responses (breast and prostate cancer). Two patients with melanoma had stable disease for > or =8 months. Histone hyperacetylation changes in peripheral blood mononuclear and tumour cells were comparable. Histone hyperacetylation seemed to correlate with pre-treatment HDAC2 expression.ConclusionThese findings suggest that vorinostat can be combined with weekly doxorubicin in this schedule at a dose of 800 mg day(-1). The HDAC2 expression may be a marker predictive of HDAC inhibition. Antitumor activity of this regimen in breast cancer, prostate cancer, and melanoma seems interesting.

Ecological processes occur over multiple spatial, temporal and thematic scales in three-dimensional (3D) ecosystems. Characterizing and monitoring change in 3D structure at multiple scales is challenging within the practical constraints of conventional ecological tools. Remote sensing from satellites and crewed aircraft has revolutionized broad-scale spatial ecology, but fine-scale patterns and processes operating at sub-metre resolution have remained understudied over continuous extents. We introduce two high-resolution remote sensing tools for rapid and accurate 3D mapping in ecology-terrestrial laser scanning and structure-from-motion photogrammetry. These technologies are likely to become standard sampling tools for mapping and monitoring 3D ecosystem structure across currently under-sampled scales. We present practical guidance in the use of the tools and address barriers to widespread adoption, including testing the accuracy of structure-from-motion models for ecologists. We aim to highlight a new era in spatial ecology that uses high-resolution remote sensing to interrogate 3D digital ecosystems.

Objectives: Although both radiation therapy and chemotherapy are frequently used to treat locally advanced pancreatic cancer (LAPC) patients, the role of radiation therapy remains controversial with data evaluating its efficacy mostly derived from small randomized trials. In this study, we evaluate the survival benefit of radiation therapy using SEER dataset in patients with LAPC., Materials and Methods: The SEER Registry dataset from 2004 to 2011 was queried to identify LAPC (TNM stage III) patients. Patients with survival <2 months, unknown radiation status, or who received postoperative radiation were excluded. Multivariate analyses of prognostic factors related to survival were performed using a Cox proportional hazard-regression model. Propensity scores were estimated using probit regression., Results: Our search identified 4460 patients; 59% who received radiation and 41% who did not. Radiation group patients were younger (below 65 y old: 49% vs. 38%), had smaller tumor size (largest dimension <4.5 cm: 80% vs. 75%), less lymph node involvement (33% vs. 36%), and lower rate of surgical resection (4% vs. 9%). Patients who received radiation therapy had better survival (HR=0.773; 95% CI, 0.687-0.782). The 12-month overall survival in the radiation group and nonradiation group was 43% versus 29%, respectively (P<0.001). On multivariate analyses, radiation was independently associated with improved outcomes. The survival benefit with radiation was observed in propensity score-matched cohort., Conclusions: Radiation therapy was associated with improved survival. Prospective randomized trials are needed to confirm these findings. The optimal schedule and radiation type remain undetermined.

Background: While intraductal papillary mucinous neoplasms (IPMNs) with high-grade dysplasia (HGD) are thought to represent non-invasive, high-risk lesions, its natural history following resection is unknown., Methods: A retrospective review of HGD-IPMN patients (1999-2015) was performed. Recurrence patterns and clinical outcomes following pancreatectomy were analyzed and the indications for surgery were explored based on current guidelines., Results: HGD was diagnosed in 100 of 314 patients (32%) following pancreatectomy for IPMN. IPMNs were classified as main duct, branch duct, or mixed in 15, 58 and 27 patients, respectively. Following resection, 25 patients had low-risk residual disease in the remnant pancreas. With a median follow-up of 35 months (range 1-129), 9 patients developed progressive or recurrent disease, 4 of whom underwent additional pancreatectomy. Three patients developed invasive adenocarcinoma. Median time to recurrence was 15 months (range 7-72). Based on the management algorithm from the international consensus guidelines, resection was indicated in 76 patients (76%). Other indications for surgery included mixed-duct IPMN(13), increased cyst size(7) and other(4)., Conclusion: The prognosis of HGD-IPMN following resection is good; however, HGD may be a marker for developing IPMN recurrence or adenocarcinoma. Current guidelines regarding surgical indications for IPMN can miss a significant number of patients with HGD., (Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: Occasionally, pancreaticobiliary cancer presents as a relatively indolent disease and localized blood-borne lung metastases may be resectable. We reviewed our experience with therapeutic lung resections in pancreatic cancer patients., Methods: In a retrospective cohort study of pancreatic cancer patients who underwent subsequent therapeutic lung resections, from 1996 to 2015, all clinical data were gathered for comparison between patients undergoing pancreatic pulmonary metastasectomy and those undergoing lung resection for other diseases., Results: Among 29 patients with definitively treated pancreaticobiliary cancer who underwent lung resections with curative intent, 16 patients (55%) had resection of isolated pancreaticobiliary cancer metastases (group A) and 13 patients (45%) had 15 resections of primary lung cancers, and one granuloma (group B). No surgical complications or operative mortalities occurred. The median disease-free interval (DFI) from definitive pancreatic cancer treatment to pulmonary metastasectomy or other nonmetastasectomy therapeutic lung resection was 24.0 and 8.0 months, respectively. The estimated median overall survival after lung resection was 33 months for all patients (95% confidence interval: 0, 67) and 28 months for the group A pulmonary metastasectomy patients (95% confidence interval: 16, 40), corresponding to an estimated 5-year survival rate of 47% and 37%, respectively. Serum CA 19-9 level before lung resection significantly predicted mortality: adjusted hazard ratio 1.38 (95% confidence interval: 1.09, 1.74) per each 100-unit increment, P = .006., Conclusions: Although pancreaticobiliary cancers have an overall dismal prognosis, we recommend pulmonary metastasectomy in highly selected patients. Additionally, not all new lung masses in pancreatic cancer patients are metastases, and resection should be considered, for a second primary lung cancer is often found., (Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Without prospective data establishing a consensus multimodality approach to borderline resectable pancreatic adenocarcinoma, institutional treatment regimens vary. This study investigated the outcomes of the clinical pathway at the author's institution, which consists of neoadjuvant gemcitabine, docetaxel, capecitabine, and stereotactic radiotherapy followed by surgery., Methods: The study reviewed all cases that met the National Comprehensive Cancer Network (NCCN) diagnostic criteria for borderline resectable pancreatic adenocarcinoma from 1 January 2006, to 31 December 2013. Pancreatectomy rates, margin status, pathologic response, disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS) were retrospectively examined. Standard statistical methods and Kaplan-Meier survival analysis were used for statistical comparisons., Results: Of 121 patients who met criteria, 101 entered the clinical pathway, and 94 (93.1 %) completed neoadjuvant chemotherapy and radiation therapy. Of the 101 patients, 55 (54.5 %) underwent pancreatectomy, with 53 patients (96.4 %) having microscopically negative margins (R0) and 2 patients (3.6 %) having microscopically positive margins (R1). Vascular resection was required for 22 patients (40 %), with rates of 95.5 % for R0 (n = 21) and 4.5 % for R1 (n = 1). A pathologic response to treatment was demonstrated by 45 patients (81.8 %) and a complete response by 10 patients (14.5 %). Pancreatectomy resulted in a median DFS of 23 months (95 % conflidence interval [CI] 14.5-31.5), a median DSS of 43 months (95 % CI, 25.7-60.3), and a median OS of 33 months (95 % CI, 25.0-41.0) versus a median DSS and OS of 14 months (95 % CI, 10.9-17.1) for patients without pancreatectomy (DSS: P = 3.5 × 10(-13); OS: P = 4.7 × 10(-10))., Conclusions: The study demonstrated high rates for neoajduvant therapy completion (93.1 %) and pancreatectomy (54.5 %). After pancreatectomy, DSS was significantly improved (43 months), with a pathologic response demonstrated by 81.8 % and a complete response by 14.5 % of the patients. The results support further study of this borderline resectable pancreatic adenocarcinoma clinical pathway.

Background: Surgical resection with negative margins is the only curative approach for pancreatic cancer. A paucity of data exists in using PET/CT scan as staging workup in resectable pancreatic cancer. The aim of this study is to determine if PET/CT prevents futile laparotomy by detecting occult metastatic disease in patients with resectable or borderline resectable pancreatic cancer., Methods: Patients were included using institutional PET/CT data base incorporating National Oncologic PET Registry with diagnosis of resectable or borderline resectable pancreatic cancer from 2005 to 2012. Clinical, radiographic, and pathologic characteristics were evaluated. The impact of PET/CT on patient management was estimated by calculating the percentage of patients whose treatment plan was altered secondary to PET/CT., Results: We identified 285 patients with early stage pancreatic cancer who received PET/CT as part of initial staging workup. Upon initial workup (CT + EUS), 62% of patients were considered resectable, and 38% were borderline resectable. Addition of PET/CT scan changed the management in 10.9% (n = 31) of the patients (95% CI, 8%-15%). Metastatic lesions were confirmed with biopsy in 19 patients (61%). The proportion of change in treatment plan was significantly higher in patients who were initially considered to have borderline resectable compared with resectable malignancy (17% vs 7%, P = 0.019). In 199 patients who underwent surgery, 18.1% (n = 36) were found to have metastatic disease intraoperatively., Conclusions: PET/CT helped improve detection of occult metastases, ultimately sparing these patients a potentially unnecessary surgery. The role of PET/CT scan should be validated in prospective study.

Introduction: Pasireotide (SOM230) is a somatostatin analog with high binding affinity for somatostatin receptors including sst1, 2, 3 and 5 and inhibit insulin like growth factor-1. Blocking of IGF-1 receptor (IGF-1R) in combination with cytotoxic chemotherapy has demonstrated additive or synergistic activity in pre-clinical models. This study aimed to evaluate the maximum tolerated dose (MTD) of pasireotide in combination with standard FOLFIRI (5-fluorouracil, leucovorin and irinotecan) regimen in patients with gastrointestinal malignancies., Methods: This was a phase 1, 3 + 3 design, open-label dose escalation study conducted in sequential cohorts to determine the MTD of pasireotide in combination with FOLFIRI. All patients had gastrointestinal malignancies and were previously treated. Sixteen patients enrolled in five dose cohorts at pasireotide doses of 40, 60, 80, 100 and 120 mg were evaluated for safety and tolerability of the combination., Results: The tumor types of the enrolled subjects included esophageal (n = 5), biliary tract (n = 3), colon (n = 3), gastric (n = 2), pancreatic (n = 1), anal (n = 1) and small bowel (n = 1). No dose limiting toxicities were observed. The most common adverse events related to the study treatment included hyperglycemia (81 %), neutropenia (62 %), thrombocytopenia (44 %), anorexia (44 %), dehydration (25 %) and elevated alkaline phosphatase (25 %). Two patients had partial response and 7 patients had stable disease. Plasma levels of IGF-1 and IGFBP-3 were significantly reduced after treatment with pasireotide., Discussion: Combination of pasireotide and FOLFIRI has manageable safety profile and is feasible in patients with gastrointestinal malignancies. Preliminary signals of activity were observed. Larger phase II trials are warranted.

Objectives: Pancreatic cancer is the fourth most common cause of cancer deaths in the USA. Despite the fact that the radiotherapy in addition to chemotherapy (CT) is frequently employed, the role of chemoradiation therapy (CRT) in the treatment of locally advanced pancreatic cancer (LAPC) remains controversial. We conducted a systemic review and meta-analysis to evaluate the effect of radiation treatment in addition to CT in patients with LAPC., Methods: Only randomized controlled trials that compared CRT to CT and reported time to event summary were included in this study. The primary end point was overall survival expressed as hazard ratio (HR). Due to significant heterogeneity, random-effects model statistics were used., Results: Five eligible studies were included with a total of 593 patients (CT, N = 298; CRT, N = 295). Two studies demonstrated statistically significant difference in OS in favor of CRT and the rest of the studies did not demonstrate any significant differences. Meta-analysis demonstrated that there was a non-significant trend toward a survival benefit in the CRT arm; HR 0.913 (95 % CI 0.595-1.400, p = 0.675). No significant differences in overall results were seen with sensitivity analysis., Conclusions: The addition of radiation therapy to CT in the treatment of LAPC is associated with a non-significant trend toward survival advantage. Larger randomized controlled trials using modern CT regimens and radiation techniques are needed to further clarify the role of radiation in this setting.

Purpose: GVAX pancreas, granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells, induces T-cell immunity to cancer antigens, including mesothelin. GVAX is administered with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells. CRS-207, live-attenuated Listeria monocytogenes-expressing mesothelin, induces innate and adaptive immunity. On the basis of preclinical synergy, we tested prime/boost vaccination with GVAX and CRS-207 in pancreatic adenocarcinoma., Patients and Methods: Previously treated patients with metastatic pancreatic adenocarcinoma were randomly assigned at a ratio of 2:1 to two doses of Cy/GVAX followed by four doses of CRS-207 (arm A) or six doses of Cy/GVAX (arm B) every 3 weeks. Stable patients were offered additional courses. The primary end point was overall survival (OS) between arms. Secondary end points were safety and clinical response., Results: A total of 90 patients were treated (arm A, n = 61; arm B, n = 29); 97% had received prior chemotherapy; 51% had received ≥ two regimens for metastatic disease. Mean number of doses (± standard deviation) administered in arms A and B were 5.5 ± 4.5 and 3.7 ± 2.2, respectively. The most frequent grade 3 to 4 related toxicities were transient fevers, lymphopenia, elevated liver enzymes, and fatigue. OS was 6.1 months in arm A versus 3.9 months in arm B (hazard ratio [HR], 0.59; P = .02). In a prespecified per-protocol analysis of patients who received at least three doses (two doses of Cy/GVAX plus one of CRS-207 or three of Cy/GVAX), OS was 9.7 versus 4.6 months (arm A v B; HR, 0.53; P = .02). Enhanced mesothelin-specific CD8 T-cell responses were associated with longer OS, regardless of treatment arm., Conclusion: Heterologous prime/boost with Cy/GVAX and CRS-207 extended survival for patients with pancreatic cancer, with minimal toxicity., (© 2015 by American Society of Clinical Oncology.)

Purpose: We determined the safety, pharmacokinetics, pharmacodynamics, and recommended phase II dose of MK-8776 (SCH 900776), a potent, selective checkpoint kinase 1 (Chk1) inhibitor, as monotherapy and in combination with gemcitabine in a first-in-human phase I clinical trial in patients with advanced solid tumor malignancies., Patients and Methods: Forty-three patients were treated by intravenous infusion with MK-8776 at seven dose levels ranging from 10 to 150 mg/m(2) as monotherapy and then in combination with gemcitabine 800 mg/m(2) (part A, n = 26) or gemcitabine 1,000 mg/m(2) (part B, n = 17). Forty percent of patients had three or more prior treatment regimens, and one third of patients had previously received gemcitabine., Results: As monotherapy, MK-8776 was well tolerated, with QTc prolongation (19%), nausea (16%), fatigue (14%), and constipation (14%) as the most frequent adverse effects. Combination therapy demonstrated a higher frequency of adverse effects, predominantly fatigue (63%), nausea (44%), decreased appetite (37%), thrombocytopenia (32%), and neutropenia (24%), as well as dose-related, transient QTc prolongation (17%). The median number of doses of MK-8776 administered was five doses, with relative dose-intensity of 0.96. Bioactivity was assessed by γ-H2AX ex vivo assay. Of 30 patients evaluable for response, two showed partial response, and 13 exhibited stable disease., Conclusion: MK-8776 was well tolerated as monotherapy and in combination with gemcitabine. Early evidence of clinical efficacy was observed. The recommended phase II dose is MK-8776 200 mg plus gemcitabine 1,000 mg/m(2) on days 1 and 8 of a 21-day cycle., (© 2015 by American Society of Clinical Oncology.)

Purpose. Patients with large >5 cm, high-grade resectable soft tissue sarcomas (STS) have the highest risk of distant metastases. Previously we have shown that dendritic cell (DC) based vaccines show consistent immune responses. Methods. This was a Phase I single institution study of neoadjuvant radiation with DC injections on 18 newly diagnosed high-risk STS patients. Neoadjuvant treatment consisted of 50 Gy of external beam radiation (EBRT), given in 25 fractions delivered five days/week, combined with four intratumoral injections of DCs followed by complete resection. The primary endpoint was to establish the immunological response to neoadjuvant therapy and obtain data on its clinical safety and outcomes. Results. There were no unexpected toxicities or serious adverse events. Twelve out of 18 (67%) patients were alive, of which an encouraging 11/18 (61%) were alive with no systemic recurrence over a period of 2-8 years. Favorable immunological responses correlated with clinical responses in some cases. Conclusions. This study provides clinical support to using dendritic cell injections along with radiation in sarcomas, which when used optimally in combination can help clinical outcomes in soft tissue sarcoma. Study registration number is NCT00365872.

Pancreatic cancer is an extremely aggressive malignancy with a dismal prognosis. Cancer patients and tumor-bearing mice have multiple immunoregulatory subsets including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC) that may limit the effectiveness of anti-tumor immunotherapies for pancreatic cancer. It is possible that modulating these subsets will enhance anti-tumor immunity. The goal of this study was to explore depletion of immunoregulatory cells to enhance dendritic cell (DC)-based cancer immunotherapy in a murine model of pancreatic cancer. Flow cytometry results showed an increase in both Tregs and MDSC in untreated pancreatic cancer-bearing mice compared with control. Elimination of Tregs alone or in combination with DC-based vaccination had no effect on pancreatic tumor growth or survival. Gemcitabine (Gem) is a chemotherapeutic drug routinely used for the treatment for pancreatic cancer patients. Treatment with Gem led to a significant decrease in MDSC percentages in the spleens of tumor-bearing mice, but did not enhance overall survival. However, combination therapy with DC vaccination followed by Gem treatment led to a significant delay in tumor growth and improved survival in pancreatic cancer-bearing mice. Increased MDSC were measured in the peripheral blood of patients with pancreatic cancer. Treatment with Gem also led to a decrease of this population in pancreatic cancer patients, suggesting that combination therapy with DC-based cancer vaccination and Gem may lead to improved treatments for patients with pancreatic cancer.

Context: Cyst fluid CEA concentration>192 ng/mL has proven accurate to differentiate mucinous from non-mucinous pancreatic cystic neoplasms. It is unclear whether the degree of cyst fluid CEA elevation is predictive of malignant behavior in IPMNs., Objectives: To determine whether elevated cyst fluid CEA concentrations were predictive of invasive cancer., Design: Cross sectional study., Setting: Single National Cancer Institute comprehensive cancer care center experience., Patients: 47 patients underwent preoperative EUS-FNA with cyst fluid analysis and surgical resection of an IPMN over a 9 year period., Main Outcome Measurements: Cyst fluid CEA concentrations among the four grades associated with IPMN (low grade dysplasia, moderate dysplasia, high grade dysplasia, and invasive cancer)., Results: The mean±standard deviation cyst fluid CEA concentration increased as the pathology progressed from low grade dysplasia (1,261±1,679 ng/mL) to moderate dysplasia (7,171±22,210 ng/mL) to high grade dysplasia (10,807±36,203 ng/mL). However, the mean CEA level decreased (462±631 ng/mL) once invasive cancer developed (P=0.869). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of a cyst fluid CEA concentration greater than 200 ng/mL for the diagnosis of malignant IPMN (cases of high grade dysplasia and invasive IPMN) was 52.4%, 42.3%, 42.3%, 52.4% and 46.8%, respectively., Limitations: Single center experience, small patient numbers, retrospective data collection., Conclusion: The degree of cyst fluid CEA elevation is a poor predictor of malignant degeneration within IPMNs. Clinical management decisions regarding surgical resection should not be based upon degree of cyst fluid CEA elevation.

Background and Objectives: To improve the likelihood of achieving a margin-free resection, neoadjuvant induction chemotherapy with GTX (gemcitabine, docetaxel, and capecitabine) followed by 5-FU-IMRT was administered to patients with borderline resectable pancreatic cancer. The utility of computed tomography (CT), endoscopic ultrasound (EUS), positron emission tomography (PET), and CA 19-9 during diagnostic workup and assessment of response was also examined., Methods: Seventeen patients with borderline resectable pancreatic cancer received a median of three cycles of neoadjuvant GTX induction chemotherapy followed by 5-FU-IMRT with dose painting. CA 19-9, CT mass size, and PET SUV were examined before and after neoadjuvant treatment., Results: Diagnostic EUS and CT scans displayed similar mean mass sizes and extent of vascular involvement. Eight of the 17 patients achieved an R0 resection. Median CA 19-9 levels, CT mass size, and PET SUV all significantly decreased after neoadjuvant therapy. The median progression-free survival and overall survival were 10.48 and 15.64 months, respectively. Six patients are still alive., Conclusions: Neoadjuvant GTX induction chemotherapy followed by 5-FU-IMRT shows promise in improving the likelihood of resectability with negative margins in borderline resectable pancreatic cancer. CT and EUS play complimentary roles during diagnostic workup. CT scans, CA 19-9, and PET scans are useful in judging response to neoadjuvant therapy., (Copyright © 2011 Wiley-Liss, Inc.)

Compared with multileaf collimator (MLC)-based intensity-modulated radiotherapy (IMRT) for moving targets, compensator-based IMRT has advantages such as shorter beam-on time, fewer monitor units with potentially decreased secondary carcinogenesis risk, better optimization-to-deliverable dose conversion, and often better dose conformity. Some of the disadvantages include additional time for the compensators to be built and delivered, as well as extra cost. Patients undergoing treatment of abdominal cancers often experience weight loss. It would be necessary to account for this change in weight with a new plan and a second set of compensators. However, this would result in treatment delays and added costs. We have developed a method to re-plan the patient using the same set of compensators. Because the weight changes seen with the treatment of abdominal cancers are usually relatively small, a new 4D computed tomography (CT) acquired in the treatment position with markers on the original isocenter tattoos can be registered to the original planning scan. The contours of target volumes from the original scans are copied to the new scan after fusion. The original compensator set can be used together with a few field-in-field (FiF) beams defined by the MLC (or beams with cerrobend blocks for accelerators not equipped with a MLC). The weights of the beams with compensators are reduced so that the FiF or blocked beams can be optimized to mirror the original plan and dose distribution. Seven abdominal cancer cases are presented using this technique. The new plan on the new planning CT images usually has the same dosimetric quality as the original. The target coverage and dose uniformity are improved compared with the plan without FiF/block modification. Techniques combining additional FiF or blocked beams with the original compensators optimize the treatment plans when patients lose weight and save time and cost compared with generating plans with a new set of compensators., (Copyright © 2011 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Purpose: CT-2106 is a 20(S)-camptothecin poly-L-glutamate conjugate. This linkage stabilizes the active lactone form of camptothecin and enhances aqueous solubility. In addition, poly-L-glutamate is postulated to increase tumor delivery of the active compound through enhanced permeability and retention effect in tumor. We studied a weekly schedule of CT-2106 in patients with refractory solid tumor malignancies., Experimental Design: CT-2106 was infused (10 min i.v. infusion) on days 1, 8, and 15 of each 28-day cycle. Plasma and urine were analyzed for total and unconjugated camptothecin by high-performance liquid chromatography equipped with a fluorescence detector. Toxicity and response assessments were done with Common Toxicity Criteria for Adverse Events version 3 and Response Evaluation Criteria in Solid Tumors, respectively., Results: Twenty-six patients were enrolled. Median age was 58 years (range, 36-83) and median number of doses was 6 (range, 1-9). The most frequent tumor type (50%) was melanoma. Dose limiting toxicities were thrombocytopenia and fatigue. A weekly dose of 25 mg/m2 given every 3 of 4 weeks was the maximum tolerated dose. The majority of grade 3 and 4 toxicities were hematologic. The pharmacokinetic profile of conjugated and unconjugated camptothecin showed a polyexponential decline with similar terminal half life (t1/2 range was 44-63 and 31-48 h for conjugated and unconjugated, respectively). Pharmacokinetics of conjugated and unconjugated camptothecin were dose and time independent in the tested dose range. Urinary excretion of conjugated and unconjugated camptothecin accounted for about 30% and 4% of the administered dose, respectively., Conclusions: CT-2106 has a more manageable toxicity profile compared with unconjugated camptothecin. The maximum tolerated dose is 25 mg/m2 weekly given 3 of 4 weeks. This compound results in prolonged release of unconjugated camptothecin.

cAMP (3',5' cyclic adenosine monophosphate) is a second messenger that in eukaryotic cells induces physiological responses ranging from growth, differentiation, and gene expression to secretion and neurotransmission. Most of these effects have been attributed to the binding of cAMP to cAMP-dependent protein kinase A (PKA). Here, a family of cAMP-binding proteins that are differentially distributed in the mammalian brain and body organs and that exhibit both cAMP-binding and guanine nucleotide exchange factor (GEF) domains is reported. These cAMP-regulated GEFs (cAMP-GEFs) bind cAMP and selectively activate the Ras superfamily guanine nucleotide binding protein Rap1A in a cAMP-dependent but PKA-independent manner. Our findings suggest the need to reformulate concepts of cAMP-mediated signaling to include direct coupling to Ras superfamily signaling.

Ras proteins, key regulators of growth, differentiation, and malignant transformation, recently have been implicated in synaptic function and region-specific learning and memory functions in the brain. Rap proteins, members of the Ras small G protein superfamily, can inhibit Ras signaling through the Ras/Raf-1/mitogen-activated protein (MAP) kinase pathway or, through B-Raf, can activate MAP kinase. Rap and Ras proteins both can be activated through guanine nucleotide exchange factors (GEFs). Many Ras GEFs, but to date only one Rap GEF, have been identified. We now report the cloning of a brain-enriched gene, CalDAG-GEFI, which has substrate specificity for Rap1A, dual binding domains for calcium (Ca2+) and diacylglycerol (DAG), and enriched expression in brain basal ganglia pathways and their axon-terminal regions. Expression of CalDAG-GEFI activates Rap1A and inhibits Ras-dependent activation of the Erk/MAP kinase cascade in 293T cells. Ca2+ ionophore and phorbol ester strongly and additively enhance this Rap1A activation. By contrast, CalDAG-GEFII, a second CalDAG-GEF family member that we cloned and found identical to RasGRP [Ebinu, J. O., Bottorff, D. A., Chan, E. Y. W., Stang, S. L., Dunn, R. J. & Stone, J. C. (1998) Science 280, 1082-1088], exhibits a different brain expression pattern and fails to activate Rap1A, but activates H-Ras, R-Ras, and the Erk/MAP kinase cascade under Ca2+ and DAG modulation. We propose that CalDAG-GEF proteins have a critical neuronal function in determining the relative activation of Ras and Rap1 signaling induced by Ca2+ and DAG mobilization. The expression of CalDAG-GEFI and CalDAG-GEFII in hematopoietic organs suggests that such control may have broad significance in Ras/Rap regulation of normal and malignant states.

Substance use among a random sample of mentally ill, community-based patients was examined. Current use was found to have declined substantially from a high lifetime prevalence, and a family history of substance abuse was associated with moderate to heavy use. No association was found between heavy substance use and elevated psychopathology, hospitalization, or medication noncompliance. Hospital admissions and some symptoms were less prevalent among users preferring marijuana.