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Background: Immune mechanisms have been implicated in the pathogenesis of depression. Translocator protein (TSPO)–targeted positron emission tomography (PET) has been used to assess neuroinflammation in major depressive disorder. We aimed to 1) test the hypothesis of significant case-control differences in TSPO binding in the anterior cingulate cortex, prefrontal cortex, and insula regions; and 2) explore the relationship between cerebral TSPO binding and peripheral blood C-reactive protein (CRP) concentration. Methods: A total of 51 depressed subjects with Hamilton Depression Rating Scale score >13 (median 17; interquartile range, 16–22) and 25 healthy control subjects underwent dynamic brain 11C-PK11195 PET and peripheral blood immune marker characterization. Depressed subjects were divided into high CRP (>3 mg/L; n = 20) and low CRP (2 p = .09; F 1,71 = 6.97, p = .01), which was not influenced by body mass index. The case-control difference was greatest in the anterior cingulate cortex (d = 0.49; t 74 = 2.00, p = .03) and not significant in the prefrontal cortex or insula (d = 0.27 and d = 0.36, respectively). Following CRP stratification, significantly higher TSPO binding was observed in low-CRP depression compared with controls (d = 0.53; t 54 = 1.96, p = .03). These effect sizes are comparable to prior major depressive disorder case-control TSPO PET data. No significant correlations were observed between TSPO and CRP measures. Conclusions: Consistent with previous findings, there is a modest increase in TSPO binding in depressed patients compared with healthy control subjects. The lack of a significant correlation between brain TSPO binding and blood CRP concentration or body mass index poses questions about the interactions between central and peripheral immune responses in the pathogenesis of depression.

BACKGROUND: Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study.METHODS: GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968.FINDINGS: 1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6-69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0-79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2-51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9-90·8) in PET complete responders and 72·0% (63·1-79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3-0·6, pINTERPRETATION: Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed.FUNDING: F Hoffmann-La Roche.

The Metrolink phase 3 project in Manchester, UK, has created around 60 km of new tram lines and has incorporated over 380 structures including 160 bridges and tunnels. Nearly 80 bridges were refurbished, repaired or strengthened to provide a low-maintenance system with a minimum 50-year structural design life. The new tram lines have been built on new dedicated alignments and on former railway corridors, reusing existing structures with an age of up to 140 years. Various contractual and technical approaches were taken to address the risk due to structure condition, including risk-sharing arrangements and phased scope determination. Particular issues encountered by the project include: limited information on structure condition; corrosion of metallic structures; scope risk; strategy for repair versus replacement; vehicle incursion risk; determining appropriate specifications; retention of cast-iron structures and modifications to parapets due to electrification. The conclusions include lessons learned for projects dealing with the renewal and upgrade of legacy structures in an affordable manner.

From January 1992 through May 1993, 31 patients with adenocarcinoma of the pancreas or hepatocellular carcinoma were treated with weekly oral methotrexate (7.5 mg/M2 every 6 hours for 6 doses) and continuous oral AZT (200 mg four times daily). Patients were treated for a total of 6 months or until disease progression. The median age was 66 (range 44-79) and the median KPS was 80. No patient had received prior chemotherapy. Hematologic toxicity was severe with 50% of patients developing hemoglobins less than 8 gm/dl and 70% with granulocyte counts less than 1000 per mm3. One patient achieved a radiographic complete remission and 2 had stable disease. Two-thirds of patients progressed within 2 months of beginning therapy. The combination of methotrexate and AZT is an inactive regimen in pancreatic and hepatocellular carcinoma and is associated with considerable toxicity.

BACKGROUND. Ovarian tumors frequently express c-Kit and/or platelet-derived growth factor receptors (PDGFRs). Imatinib mesylate blocks the growth of ovarian cancer cells in vitro and may enhance the activity of chemotherapy. This study was conducted to determine the activity of imatinib in combination with docetaxel in patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC). METHODS. Eligible patients had recurrent, platinum-resistant, or refractory EOC that expressed PDGFRα or c-kit, as determined by immunohistochemistry. Imatinib mesylate at a dose of 600 mg orally once daily was administered continuously with docetaxel at a dose of 30 mg/m2 given intravenously once weekly in Weeks 1 through 4 of every 6-week cycle. The primary endpoint was objective response rate (ORR) as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS. Thirty-four patients were screened for PDGFRα and c-kit expression to enroll 23 patients between December 2003 and October 2005. Four patients had c-kit-positive/PDGFR-negative tumors, 11 patients had PDGFR-positive/c-kit-negative tumors, and 8 patients had c-kit-positive/PDGFR-positive tumors. The median patient age was 56 years (range, 33-76 years). Patients had received a median of 3 prior treatments. The ORR was 21.7% and included 1 complete and 4 partial responses. An additional 3 patients had stable disease for more than 4months. Expression of PDGFR, c-kit, phosphatase and tensin homolog (PTEN), and phosphorylated protein kinase B (Akt) did not predict response to therapy. The most common adverse events encountered were fatigue (83%), nausea (74%), diarrhea (61%), anorexia (52%), and edema (65%), and the majority of those events were graded as grade 1 or 2. CONCLUSIONS. The combination imatinib and docetaxel was tolerated in patients with heavily pretreated EOC that expressed c-kit or PDGFRα. Few patients had sustained responses or stable disease. Cancer 2008. © 2008 American Cancer Society.

The purpose of this study is to determine the control of acute and delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy (MEC) and highly emetogenic chemotherapy (HEC) with the combined use of palonosetron and olanzapine, and dexamethasone with the dexamethasone given on day 1 only. Forty chemotherapy-naive patients received on the day of chemotherapy, day 1, an anti-emetic regimen consisting of dexamethasone, palonosetron, and olanzapine. Patients continued olanzapine for days 2–4 after chemotherapy administration. Patients recorded daily episodes of emesis, daily symptoms utilizing the M.D. Anderson Symptom Inventory, and the utilization of rescue therapy. For the first cycle of chemotherapy, the complete response (no emesis, no rescue) for the acute period (24 h post-chemotherapy) was 100%, the delayed period (days 2–5 post-chemotherapy) 75%, and the overall period (0 120 h post-chemotherapy) 75% in 8 patients receiving HEC and was 97, 75, and 72% in 32 patients receiving MEC. Patients with no nausea for the acute period was 100%, the delayed period 50%, and the overall period 50% in 8 patients receiving HEC and was 100, 78, and 78% in 32 patients receiving MEC. The complete response and control of nausea in subsequent cycles of chemotherapy were not significantly different from cycle one. Olanzapine combined with a single dose of dexamethasone and a single dose of palonosetron was very effective in controlling acute and delayed CINV in patients receiving both HEC and MEC.

Thirty patients with advanced renal cell carcinoma were treated on a phase 11 trial with altretamine. Altretamine was administered orally at a dosage of 260 mg/m2 days 1 through 14 with cycles repeated every 28 days. Nausea and vomiting were the most common toxicities. Ten percent (3 of 30) experienced Grade 3 gait abnormalities. None of the thirty evaluable patients achieved a complete or partial response. In summary, altretamine did not show antitumor activity in the treatment of advanced renal cell carcinoma.

BACKGROUND Between August 1984 and November 1989, the Hoosier Oncology Group conducted a Phase III study comparing cyclophosphamide (CTX) with cyclophosphamide, doxorubicin, and methotrexate (CAM) in patients with hormone-refractory metastatic prostatic cancer to determine whether the addition of doxorubicin and methotrexate to the cyclophosphamide regimen conferred any survival advantage. METHODS One hundred three patients were registered and randomized, 99 were evaluable for response, and all were evaluable for survival results. All had histologically confirmed metastatic prostatic cancer and had not responded to hormonal therapy. Fifty-three patients received CTX alone, and 50 received CAM. Seventy-one patients (69%) had evaluable disease, and 32 (31%) had measurable disease. RESULTS There were no complete responses and only four (13%) partial responses in the patients with measurable disease. There was no difference in overall survival time between the two treatment arms in either patients with a Karnofsky performance status (KPS) of 80-100 (median survival, 9.0 versus 9.5 months; P = 0.93) or in those with a KPS of 50-70 (median survival, 5.0 versus 6.0 months; P = 0.51). There was no difference in overall time to progression between the two treatment arms (median time to progression; 4.4 versus 6.2 months; P = 0.07). Toxicity was tolerable in both regimens. CONCLUSIONS It was concluded that there was no survival advantage to CAM over CTX alone. New chemotherapeutic agents with greater activity against prostatic cancer must be identified.

5091 Background: Ovarian tumors harborc-Kit and PDGF receptors. We showed in an in-vitro model that Imatinib (G) inhibits the growth of ovarian cancer cells. We hypothesized that G in combination with chemotherapy inhibits the growth of ovarian tumors. Data from a phase II clinical trial utilizing G in combination with Docetaxel (D) in patients with advanced ovarian cancer (OC) are presented. Methods: This was an open label, one stage, multi-center phase II clinical trial. Planned sample size was 23. Patients with relapsed, platinum-resistant or refractory OC expressing PDGFR or c-kit were eligible. PDGFR and c-kit expression was assessed prior to enrollment by IHC using archival tumor tissue. G was administered at 600mg/d continuously and D was given weekly (30mg/m2) for 4 weeks, with 2 weeks break. Each cycle was 6 weeks, with a maximum of 6 cycles allowed. Tumor assessments were obtained after 2, 4 and 6 cycles. Response rate by RECIST was the primary endpoint. Results: 34 patients were screened. 17 tumors were c-kit + and 25 were PDGFRα +. 23 patients were enrolled. Of those, 4 patients had c-kit+/PDGFR- tumors, 12 were PDGFR+/c-kit- and 7 were c-kit+/PDGFR+. Median age was 55 (range 33–76) and median PS was 0 (range 0–2). Median number of prior treatments was 3 (range 1–9). Efficacy and toxicity data are available for 20 and 14 patients, respectively. Based on RECIST, there were 3 patients with PR and 3 patients with SD lasting at least 12 weeks. Of these 6 patients, 2 pts were c-kit+, 2 were PDGFR+ and 2 were PDGFR and c-kit+. All 6 patients had carboplatin and taxane resistant disease. Grade 3–4 toxicities were: neutropenia (2), thrombocytopenia (1), fatigue (1), dehydration (1), constipation (1), cardiac ischemia (1), nausea/vomiting (2), urinary frequency (1). Other G1–2 toxicities were: N/V (9), diarrhea (7), fatigue (8), mucositis (4), anemia (4), hypocalcemia (5), rash (6), anorexia (7), edema (5), hemolysis (1), non-neutropenic infections (7). Additional data will be available in May 2006. Conclusions: The combination G+D is tolerated well. Clinical activity consisted of 3 PRs (15% response rate) and 3 SD > 3 months in pts with heavily pre-treated, platinum resistant OC expressing c-kit or PDGFRα. [Table: see text]

Background Gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR) pathway, has single agent activity in non-small cell lung cancer (NSCLC). Preclinical studies demonstrate significant interactions between the EGFR and cyclooxygenase 2 (COX-2) pathways and that simultaneous inhibition may have benefits over EGFR inhibitors alone. Methods Eligibility criteria: chemotherapy-naive, stage IIIb (with pleural effusion) or IV NSCLC, Eastern Cooperative Oncology Group Performance Status (PS) 0–1. Patients were treated with gefitinib 250 mg po daily plus celecoxib 400 mg po every 12 hours. Cycles consisted of 21-day treatment and continued until unacceptable toxicity or progression of disease. The primary objective was to evaluate the overall response rate; secondary objectives included estimation of progression free survival, overall survival, and to assess the toxicity of this regimen. Results From January 2004 to November 2004, 31 patients were enrolled: male/female 13/18; median age 70 years (range, 19–93); 68% had adenocarcinoma; Eastern Cooperative Oncology Group PS 0/1 13/18; stage IIIb/IV 2/29. Two patients died of interstitial lung disease due to treatment. There were three additional deaths during treatment that were not considered treatment related. Two additional patients discontinued treatment due to adverse events (elevated liver enzymes). Select grade 3/4 toxicities included: pneumonitis (3%), hepatic (7%), diarrhea (7%), and skin (3%). Response rate was 16% (95% CI, 5–34%), median progression free survival and overall survival were 3.2 (95% CI, 2.7–5.7 months) and 7.0 months (95% CI, 3.7–14.2 months), respectively. All responders were females with adenocarcinoma, two were remote or never smokers and three were former smokers. Conclusion Gefitinib plus celecoxib in an unselected population of chemotherapy naive patients with advanced NSCLC and a PS of 0–1 has a lower response rate and overall efficacy compared with historical controls of combination chemotherapy.