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Background While docetaxel/cisplatin/5‐fluorouracil (DCF) outperforms CF in first‐line gastric adenocarcinoma, toxicity remains an issue. Methods This multicenter phase II trial randomized chemonaïve metastatic gastric adenocarcinoma patients to fractionated weekly DCF (D 40 mg/m2, C 35 mg/m², F 1800 mg/m² over 24 h, on days 1 and 8 every 3 weeks, arm (1) or fortnightly DCF (D 50 mg/m2, C 50 mg/m², F 2000 mg/m² over 48 h every 2 weeks, arm (2). Prophylactic granulocyte colony‐stimulating factor (G‐CSF) was not allowed. The primary endpoint was the rate of febrile neutropenia within the first six treatment weeks (early FN). Results A total of 106 eligible patients were recruited. The early and overall FN rates were 9.5% and 17% in arm 1, respectively, and 5.9% and 8% in arm 2, respectively. Grade ≥3 toxicities occurred in 81% of patients in arm 1 and 90% of patients in arm 2, the most common being neutropenia (33% vs. 61%), fatigue (27% vs. 25%), vomiting (21% vs. 12%), anorexia (19% vs. 18%), and diarrhea (17% vs. 10%). Median progression‐free survival and overall survival were 5.1 (95% CI, 3.2–6.5) and 8.2 months (95% CI, 6.0–14.5), respectively, in arm 1 and 5.2 (95% CI, 3.0–6.9) and 11.9 months (95% CI, 7.4–15.9), respectively, in arm 2. Conclusions Fractionated weekly and fortnightly DCF regimens are associated with a low risk of early FN, and a better hematological toxicity profile as compared to historical DCF without compromising efficacy. Both regimens offer greater convenience removing the need for systematic use of prophylactic G‐CSF., The DoGE multicenter study randomised prospectively patients with chemonaïve gastric cancer between fractionated weekly and fortnightly DCF regimens. Both regimens are associated with a low risk of early FN, and a better hematological toxicity profile as compared to historical DCF without compromising efficacy. Both regimens offer greater convenience removing the need for systematic use of prophylactic G‐CSF.

Purpose Inoperable malignant intestinal obstruction (IMIO) is a severe complication in patients with cancer, usually gastrointestinal or gynecologic in origin. For patients with IMIO, there is a need to relieve symptoms and limit nasogastric tube (NGT) use. Previous studies have suggested the efficacy of somatostatin analogues in relieving obstruction-related symptoms, such as nausea, vomiting, and pain. The purpose of this study was to assess the efficacy of lanreotide autogel 120 mg (LAN 120 mg) in the management of symptoms resulting from IMIO in patients with advanced cancer. Methods This single-arm, multicenter study enrolled 52 patients mostly with advanced gastrointestinal or ovarian malignant tumors (35 patients with NGT and 17 patients without NGT). Patients received 1 deep subcutaneous injection of LAN 120 mg. Evaluations were performed on days 7, 14, and 28. The primary end point was the percentage of responding patients before or at day 7. Response was defined as ≤2 vomiting episodes per day (for patients without NGT at baseline) or no vomiting recurrence (after NGT removal) during at least 3 consecutive days at any time point between treatment and day 7. Responders at day 28 were offered a second LAN 120 mg injection and followed up until day 56. Findings The proportion of responders in the intention-to-treat population was 24 of 52 (46.2%), which was significantly greater than the reference proportion of 30% (P = 0.0055). Patients without NGT had a higher response (88.2%) than patients with NGT (25.7%) and had a steady trend for clinical improvement that led to sustainable responses. Median time to response was 9 days for the overall population, 3 days for patients without NGT, and 14 days for patients with NGT (P Implications Our study is the first to use long-acting LAN 120 mg in patients with IMIO and suggests an effect in controlling clinical symptoms in patients with and without NGT at baseline. The safety profile of LAN 120 mg was similar to that reported in other indications. ClinicalTrials.gov identifier: NCT02275338.

Predictive factors for adverse events in metastatic colorectal cancer patients treated with regorafenib are currently lacking. In this safety analysis of a prospective phase II clinical trial, we assess the association between several clinical, laboratory, and imaging parameters and the occurrence of adverse events. Our results show that female sex is an independent risk factor for increased toxicity. Background: Regorafenib is a standard treatment for refractory metastatic colorectal cancer (mCRC). In view of the toxicity burden, significant research efforts have been made to increase the therapeutic ratio of this multikinase inhibitor. Predictive factors for treatment-related adverse events (TRAEs), however, are still lacking. Materials and Methods: We assessed the association between a number of baseline clinical, laboratory and imaging parameters and the occurrence of TRAEs in 136 patients who had received regorafenib (160 mg/day, 3-weeks-on/1-week-off) in a prospective phase II clinical trial. Results: Grade >= 2 TRAEs during the first cycle of treatment (84% vs. 60%, P=.002) and grade >= 3 TRAEs throughout the whole treatment (71% vs. 53%, P=.035) occurred more frequently in females, with sex being the only independent predictive factor of early and any-time toxicity (OR 3.4; 95% CI: 1.2-11.1, P=.02 and OR 2.1; 95% CI: 1.0-4.4, P=.045, respectively). Fatigue, anorexia, hypertension, and rash were reported significantly more frequently by females than males (P

SCOPUS: le.j, info:eu-repo/semantics/published

Biliary tract and gallbladder cancers are rare tumors with a poor prognosis (except the ampulla type). The evolution of hepatobiliary cancer incidence varies widely around the world. According to the Belgian Cancer Registry, the number of hepatobiliary cancers has increased every year since 2004. This retrospective study included patients diagnosed with cholangiocarcinoma, ampulla cancer, or gallbladder cancer at the university hospital, CHU UCL, Godinne site, in Namur, Belgium, between 1997 and 2017. The evolution of cancer incidence was evaluated with the Mann-Kendall method, by analyzing 7 consecutive 3-year periods. We calculated survival with the Kaplan-Meier method, and we determined prognostic factors with the log-rank test and Cox models. Between 1997 and 2017, we included 128 patients that were newly diagnosed in our center. According to the Mann-Kendall test, the evolution of the incidence of these cancers in our hospital increased significantly over the study period (Sen's slope = 7; p = 0.003). The 1-year overall survival was 53.0 ± 4.7%. Poor prognostic factors included age, cancer stage, local cancer extension, and metastatic disease. The independent prognostic factors of survival were age (p = 0.002), ampulla cancer (p

Individual patients' survival varies greatly in metastatic castration-resistant prostate cancer. Retrospective analysis of 368 patients treated with docetaxel and starting abiraterone acetate revealed 5 adverse prognostic factors: hemoglobin < 12 g/dL, > 10 metastases, ECOG performance status >= 2, radiographic progression, and time since diagnosis < 90 months. A prognostic model stratifies patients into 3 groups with different estimated survival, which can aid in patient counseling.Abiraterone acetate (AA) increases overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel. However, survival time varies substantially between individuals. Our goal was to identify prognostic factors that better estimate OS. Materials and Methods: This is a retrospective multicentric analysis of 368 patients with mCRPC starting AA with prednisone after docetaxel. Cox proportional hazards statistics were applied. A multivariate model was constructed based on significant univariate predictors by using a manual stepwise forward and backward selection strategy. Model performance was determined by using receiver operating characteristic (ROC) curves. Results: Univariate analysis identified 20 significant OS predictors. A multivariate model was constructed, based on 220 patients, incorporating 5 independent risk factors for decreased OS at the time of AA initiation: hemoglobin 10 metastases (HR 1.80), ECOG performance status >= 2 (HR 1.88), radiographic progression (HR 1.50), and time since diagnosis < 90 months (HR 1.66, all P

Objective: To describe a rare pathology, the liposarcoma of the spermatic cord (LSC), and discuss its diagnosis and treatment. Materials and Methods: We report a case of well-differentiated LSC in a 61-year-old man. The main complaint was painless enlargement in the right inguinoscrotal area that appeared 6 months prior to presentation. Ultrasonography showed a heterogeneous and hyperechogenic mass of the right spermatic cord that was highly suspicious of malignancy. Computed tomography confirmed a heterogeneous supratesticular mass. The mass was surgically removed. Results: Pathological examination showed a well-differentiated LSC. The patient did not receive any additional treatment. The follow-up did not present complications or further symptoms and, at present, the patient is in complete remission. Conclusion: LCSs are a very rare entity. The diagnosis is difficult and often mistaken with common scrotal swelling associated with a hernia, hydrocele, or other tumour. Treatment should include complete surgical excision, usually by radical inguinal orchiectomy. A long follow-up period is necessary.

TMEM45A is a transmembrane protein involved in tumor progression and cancer resistance to chemotherapeutic agents in hypoxic condition. It is correlated to a low breast cancer patient overall survival. However, little is known about this protein, in particular the mechanisms by which TMEM45A modulates cancer cell chemosensitivity. In this work, the messenger RNA expression of TMEM45A was assessed in head and neck squamous cell carcinoma (HNSCC) and renal cell carcinoma (RCC) biopsies. TMEM45A was upregulated in patients diagnosed for head and neck or renal cancer. Then, the implication of this protein in cisplatin sensitivity was explored in SQD9 and RCC4 + pVHL cells. TMEM45A inactivation decreased cell proliferation and modulated cell responses to cisplatin. Indeed, TMEM45A inactivation increased the sensitivity of SQD9 cells to cisplatin, whereas it rendered RCC4 + pVHL cells resistant to this anticancer agent. Through RNA-sequencing analysis, we identified several deregulated pathways that indicated that the impact on cisplatin sensitivity may be associated to the inhibition of DNA damage repair and to UPR pathway activation. This study demonstrated, for the first time, an anti or a pro-apoptotic role of this protein depending on the cancer type and highlighted the role of TMEM45A in modulating patient responses to treatment.

3600 Background: ctDNA is an indicator of minimal residual disease and negative prognostic factor in stage II-III CC treated with surgery +/- adjuvant chemotherapy (CT). No study, however, has ever analysed the prognostic value of this biomarker in CC patients (pts) treated with NACT. We sought to evaluate the prognostic value of baseline and early changes of cf/ctDNA in stage II-III CC pts who were treated with one cycle of NA FOLFOX CT followed by surgery +/- adjuvant FOLFOX CT in the PePiTA trial. Methods: PePiTA was a multicentre, single-arm, prospective phase II trial testing in vivo tumour chemosensitivity of early stage CC (as assessed by 18F-FDG PET/CT-based metabolic response to one cycle of NA FOLFOX) and its association with long-term outcome (NCT00994864). Plasma samples were prospectively collected at baseline, 2 weeks after one cycle of NA FOLFOX CT, and before surgery. NPY and WIF1 were selected as universal methylation markers for ctDNA and analysed with digital droplet (dd)PCR technology. Data from ddPCR were processed with the QuantaSoft v1.6 software (Bio-Rad). Survival outcome measures were 5-year disease-free survival (DFS) and 6-year overall survival (OS). ROC curve analyses, Kaplan-Meier method, cox proportional hazards models and log-rank tests were used. Statistical analyses were carried out with SPSS v25.0 (SPSS Inc.). Results: 80 pts were included (44 ypStage I-II and 36 ypStage III). After a median follow-up of 52.5 months, 5-year DFS and 6-year OS were 68% (95%CI 52-84) and 84% (95%CI 74-94), respectively. Pts with high (≥1600 ng/ml) baseline cfDNA had worse 6-year OS (HR 6.45, 95%CI 1.61-25.84; p = 0.008). Early changes of cfDNA after one cycle of NA FOLFOX CT failed to predict survival (HR DFS 0.96, 95%CI 0.38-2.43; p = 0.92; HR OS 0.62, 95%CI 0.16-2.50; p = 0.50). At baseline, 25 out of 60 (42%) ctDNA-assessable patients were positive. Detectable ctDNA at baseline (HR DFS 2.06, 95%CI 0.65-6.49; p = 0.22; HR OS 3.11, 95%CI 0.57-16.99; p = 0.19) or at any timepoint before surgery (HR DFS 1.65, 95%CI 0.54-5.04; p = 0.38; HR OS 2.80, 95%CI 0.54-14.44; p = 0.22) was not significantly associated with survival. A trend toward a significant association between ctDNA increase at surgery and 5-year DFS was found (HR 3.66, 95%CI 0.81-16.44; p = 0.09). Data on the correlation between early changes of cf/ctDNA and 18F-FDG PET/CT-based metabolic response will be presented at the meeting. Conclusions: For the first time, we have shown that baseline cfDNA may predict survival outcome in early stage CC pts treated with NACT. Pending confirmation in larger series, testing for cfDNA at baseline could help select high-risk pts who may benefit from FOxTROT-like, NACT treatment strategies. While analysis of ctDNA in this setting did not appear useful to predict prognosis, these results might be secondary to the small sample size.

Predictive biomarkers are eagerly awaited in advanced colorectal cancer (aCRC). Targeted sequencing performed on tumor and baseline plasma samples in 20 patients with aCRC treated with regorafenib identified 89 tumor-specific mutations of which ≥50% are also present in baseline plasma. Droplet digital PCR (ddPCR) assays were optimized to monitor circulating tumor DNA (ctDNA) levels in plasmatic samples collected throughout the treatment course and showed the importance of using the absolute value for ctDNA rather than the mutant/wild type ratio in monitoring the therapy outcome. High baseline cell free DNA (cfDNA) levels are associated with shorter overall survival (OS) (HR 7.38, P=0.001). An early increase (D14) in mutated copies/mL is associated with a significantly worse PFS (HR 6.12, P=0.008) and OS (HR 8.02, P=0.004). These data suggest a high prognostic value for early ctDNA level changes and support the use of blood-born genomic markers as a tool for treatment., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Growing teratoma syndrome is a rare syndrome that affects patients with nonseminomatous germ-cell tumors (NSGCTs). It is characterized by recurrent growing masses that appear during or after chemotherapy in the presence of normal levels of tumor markers. Histological examination is the only way to confirm the diagnosis. Case Presentation: We present the case of a 36-year-old man who developed recurrent masses after curative treatment for NSGCT of the testicle. His tumor markers were normal. The patient was cured after multiple surgical procedures. Conclusions: Close follow-up after treatment for NSGCT is very important for early detection of this syndrome, which can occur even many years after tumor onset. Normal blood makers can be misleading, and surgery remains the only curative treatment.

The incidence of thyroid cancer has increased markedly in recent decades, but has been stable in terms of mortality rates. For the most part, these cancers are treated with surgery, which may or may not be followed by radioactive iodine depending on the tumor subtype. Still, many of these cancers will recur and may be treated with radioactive iodine or another surgery. It is unclear what treatment is best for cases of locally advanced or metastatic thyroid cancer that are refractory to radioactive iodine. Chemotherapy has a very low response rate. However, in the past few years, several systemic therapies, primarily targeted, have emerged to improve the overall survival of these patients. Alternative treatments are also of interest, namely peptide receptor radionuclide therapy or immunotherapy.

Background We assessed safety, immunogenicity and clinical activity of recombinant MAGE-A3 antigen combined with AS15 immunostimulant (MAGE-A3 immunotherapeutic) in association with dacarbazine in patients with metastatic melanoma. Methods In this open-label, phase I/II, uncontrolled multicentre trial conducted in Belgium and France, patients with MAGE-A3-positive melanoma received up to 24 doses of MAGE-A3 immunotherapeutic (four cycles) coadministered with eight doses of dacarbazine. Adverse events (AE) were recorded until 31 days postvaccination, and serious AEs (SAE), until 30 days following the last dose. MAGE-A3-specific antibodies were measured by ELISA. Clinical activity of MAGE-A3 immunotherapeutic was assessed in patients positive/negative for previously identified gene signature (GS) associated with clinical outcome. Results Forty-eight patients were enrolled and treated (32 GS+, 15 GS−, 1 unknown GS status); two patients completed the study. All patients reported AEs, the most common were ‘general disorders and administration site conditions’ (94%). Treatment-related AEs were reported by 85% of patients; the most common was pain at injection site (38%). Sixteen SAEs were reported by 21% of patients; two were considered as treatment related (neutropenia and thrombocytopenia; grade 4). Postdose 4, all patients were seropositive for MAGE-A3-specific antibodies, with a geometric mean titre of 2778.7 ELISA units (EU)/mL (95% CI 1638.3 to 4712.8). One complete and three partial responses were reported (only in GS+ patients). Median overall survival was 11.4 months for GS+ and 5.3 months for GS− patients. Conclusion Although this trial shows poor results compared with the new results with checkpoint inhibitors, it gives an interesting insight in rapidly developing fields like combinations of immunotherapy and chemotherapy, new generation vaccines and the use of gene profile as a predictive marker. Trial registration number NCT00849875.

Background The survival of colorectal cancer patients is frequently determined by the extent of metastatic invasion to the liver; in cases of major involvement, therapeutic strategies are limited because the liver is necessary for drug metabolism. Material and methods We have reviewed articles about the pharmacokinetic profiles of each drug used in colorectal cancer patients with hepatic dysfunction to determine which of these treatments are most feasible. Results Some drugs appear to be feasible options for patients with hepatic insufficiency. Agents such as 5-fluorouracil and oxaliplatin, as well as monoclonal antibodies such as bevacizumab, cetuximab, and panitumumab, can potentially be used in these cases. On the other hand, irinotecan and regorafenib cannot be recommended because of the risk of increased toxicity. Conclusion Treatment of patients with colorectal cancer and liver dysfunction represents a major challenge because the prognosis is usually very poor and alteration of liver function is normally an exclusion criterion in clinical trials. In this review, we present evidence regarding the use of each drug in patients with colorectal cancer and hepatic impairment.

Background Colonoscopy is currently widely accepted as the gold standard for detection of colorectal cancer (CRC) providing detection of up to 95% of pre-cancerous lesions during the procedure. However, certain limitations exist in most countries including cost and access to the procedure. Moreover, colonoscopy is an invasive technique with risk inherent to the endoscopic procedure. For this reason, alternative screening tests, in particular, fecal occult blood-based tests, have been widely adopted for frontline screening. Limited compliance to colonoscopy and fecal screening approaches has prompted research on blood-based tests as an alternative approach to identifying individuals at risk who could then be referred for colonoscopy. Increased total levels of nucleosomes in the blood have been associated with tumor burden and malignancy progression. Here, we report for the first time, CRC-associated epigenetic profiles of circulating cell-free nucleosomes (cf-nucleosomes). Methods Levels of 12 epigenetic cf-nucleosome epitopes were measured in the sera of 58 individuals referred for endoscopic screening for CRC. Results Multivariate analysis defined an age-adjusted panel of four cf-nucleosomes that provided an AUC of 0.97 for the discrimination of CRC from healthy controls with high sensitivity at early stages (sensitivity of 75 and 86 at 90% specificity for stages I and II, respectively). A second combination of four cf-nucleosome biomarkers provided an AUC of 0.72 for the discrimination of polyps from the healthy group. Conclusions This study suggests that a combination of different cf-nucleosome structures analyzed in serum samples by a simple ELISA is a promising approach to identify patients at risk of CRC. Electronic supplementary material The online version of this article (doi:10.1186/s13148-017-0351-5) contains supplementary material, which is available to authorized users.

Testicular metastases are rare in prostatic adenocarcinomas. The discovery is often fortuitous, and they are diagnosed with a histological examination. Metastasis is often confused with a primitive testicular tumor. We describe an 86-year-old patient with metastatic prostate adenocarcinoma that affected the left testis. The metastasis was discovered after Ablatherm® treatment. A prostatic origin must be suspected in a patient over 50 years old with testicular metastasis. This study highlights the importance of clinicopathological investigation and immunohistochemistry in determining the etiopathogenesis of testicular masses.

Purpose: Circulating tumor DNA (ctDNA) monitoring based on an individual mutation profile during therapy is under intense investigation in modern oncology. We previously reported that the increase of ≥50% of at least one somatic mutation among multiple monitored mutations per patient is associated with a significantly worse outcome1. This study investigates whether the ctDNA monitoring of one driver gene mutation, provides enough information as compared to multiple mutations to assess response to regorafenib in advanced chemorefractory colorectal cancer (aCRC) at an early timepoint. Experimental procedures: Archival tumor tissue and plasma samples (PL) at baseline (BL) and 14 days (D14) after treatment initiation in aCRC pts (n=141) were prospectively collected in the RegARd-C multicenter clinical trial (NCT01929616). Somatic mutations were identified based on a CRC-oriented targeted gene sequencing of tumor tissue. All available (median 2 (1-4)) driver gene mutations were monitored per patient in PL at BL and D14 via droplet digital PCR (Bio-Rad QX200 ddPCR system) to assess ctDNA dynamics. Results: In 96 evaluable patients, the most frequently monitored mutated genes were APC (73%), TP53 (72%), KRAS (66%), and PI3KCA (23%). Among patients with ≥2 monitored mutations (73/96), one was selected at random and compared to previous methodology taking in account dynamics of all followed mutations. Optimal cutoff (CO) evaluation (Contal & O’Quigley method) separated patients (n=96) according to a ctDNA increase of ≥50% versus an increase of Conclusion: The monitoring of ctDNA dynamics based on only one randomly selected driver gene mutation versus multiple is equally informative to describe adequately aCRC patients’ outcome under regorafenib after 14 days of treatment onset. Especially, combined with pre-treatment ctDNA levels, this simplifies a personalized patient monitoring. 1 P. Kehagias, et al. Circulating tumor DNA detects early response to regorafenib in advanced colorectal cancer [abstract]. AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-221 Citation Format: Pashalina Kehagias, Caroline Vandeputte, Lieveke Ameye, Hakim El Housni, Amélie Deleporte, Karen Geboes, Thierry Delaunoit, Gauthier Demolin, Marc Peeters, Lionel D'Hondt, Jos Janssens, Javier Carrasco, Maria Gomez Galdon, Pierre Heimann, Marianne Paesmans, Patrick Flamen, Alain Hendlisz. Is a single driver gene mutation sufficient for monitoring early response in advanced colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2293.

Background: Patients with cancer are particularly susceptible to drug interactions (DIs), but the extent of the problem has received limited attention. We aimed to evaluate the frequency of interactions with anticancer agents in a group of cancer patients. Methods: The study was performed in a Belgian teaching hospital. One hundred and twenty-two patients with solid malignancies were included. A comprehensive drug history was performed by a clinical pharmacist. Three renowned DI compendia were used to identify DIs. Results: Forty-one potential interactions involving an anticancer agent and considered to be clinically significant were identified among 25% of patients. The anticancer drugs mostly involved were cisplatin and methotrexate, and the most frequent co-medications involved were vitamin K antagonists, proton pump inhibitors and diuretics. In the majority of cases, the potential adverse consequence was increased toxicity of the anticancer agent and/or of the co-medication. Less than 10% of DIs were identified by the three compendia. Conclusions: Preventive measures should be taken to avoid increased toxicity or decreased efficacy of the drugs. Most of the time, this simply involves surveillance of biological or clinical parameters. Collaboration with a clinical pharmacist may be useful for the prescribing physician.

Lessons Learned Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. For the first time, cabazitaxel was investigated in incurable patients with recurrent SCCHN. Patients were randomly assigned to cabazitaxel every 3 weeks or weekly methotrexate. This phase II study did not meet its primary endpoint. Cabazitaxel has low activity in SCCHN. The toxicity profile in this population also was not favorable owing to the high rate of febrile neutropenia observed (17%). Background. Cabazitaxel is a second-generation taxane that improves the survival of patients with metastatic castrate-resistant prostate cancer following docetaxel therapy. Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. In this randomized phase II trial, we investigated cabazitaxel in patients with recurrent SCCHN. Methods. Patients with incurable SCCHN with progression after platinum-based therapy were randomly assigned to cabazitaxel every 3 weeks (cycle 1, 20 mg/m2, increased to 25 mg/m2 for subsequent cycles in the absence of nonhematological adverse events [AEs] greater than grade 2 and hematological AEs greater than grade 3) or methotrexate (40 mg/m2/week). The patients were stratified according to their performance status and previous platinum-based chemotherapy for palliation versus curative intent. The primary endpoint was the progression-free survival rate (PFSR) at 18 weeks. Results. Of the 101 patients, 53 and 48, with a median age of 58.0 years (range, 41–80), were randomly assigned to cabazitaxel or methotrexate, respectively. The PFSR at 18 weeks was 13.2% (95% confidence interval [CI], 5%–25%) for cabazitaxel and 8.3% (95% CI, 2%–20%) for methotrexate. The median progression-free survival was 1.9 months in both arms. The median overall survival was 5.0 and 3.6 months for cabazitaxel and methotrexate, respectively. More patients experienced serious adverse events with cabazitaxel than with methotrexate (54% vs. 36%). The most common drug-related grade 3–4 AE in the cabazitaxel arm was febrile neutropenia (17.3%). Conclusion. This study did not meet its primary endpoint. Cabazitaxel has low activity in recurrent SCCHN.

Background: Abiraterone acetate (AA) is licensed for treating metastatic castration-resistant prostate cancer (mCRPC). Real-world data on oncological outcome after AA are scarce. The current study assesses efficacy and safety of AA in mCRPC patients previously treated with docetaxel who started treatment during the Belgian compassionate use program (January 2011 July 2012). Patients and methods: Records from 368 patients with mCRPC from 23 different Belgian hospitals who started AA 1000 mg per day with 10 mg prednisone or equivalent were retrospectively reviewed (September 2013 December 2014). Prostate-specific antigen (PSA) response (decrease >= 50%), time to PSA progression (increase >50% over PSA nadir in case of PSA response/ >25% in absence of PSA response), time to radiographic progression (on bone scans or for soft tissue lesions using Response Evaluation Criteria In Solid Tumors 1.1), overall survival and adverse event rate (Common Terminology Criteria for Adverse Events v4.03) were analyzed. Kaplan-Meier statistics were applied. Results: Overall, 92 patients (25%) had an Eastern Cooperative Oncology Group performance status >= 2. Median age was 73 years, median PSA was 103 ng/dl. PSA response was observed in 131 patients (37.4%). Median time to PSA and radiographic progression was 4.1 months (95% CI: 3.6 /1.6) and 5.8 months (5.3-6.4), respectively. Median overall survival was 15.1 months (13.6-16.6). Most common grade 3 to 4 adverse events were anemia (13.9%), hypokalemia (7.3%), fatigue (6.8%), and pain (6.3%). Median duration of AA treatment was 5.3 months (interquartile range: 2.8-10.3). The main study limitation is its retrospective design. Conclusions: These real-world data on post-docetaxel AA efficacy are in line with the COU-AA-301 trial. Importantly, incidence of severe anemia and hypokalemia is up to 50% higher than reported in previous studies. (c) 2016 Elsevier Inc. All rights reserved.

Background: This phase II study assessed the safety and efficacy of everolimus, an oral mammalian target of rapamycin inhibitor in advanced transitional carcinoma cell (TCC) after failure of platinum-based therapy. Patients and methods: Thirty-seven patients with advanced TCC received everolimus 10 mg/day until progressive disease (PD) or unacceptable toxicity. The primary end point was the disease control rate (DCR), defined as either stable disease (SD), partial response (PR), or complete response at 8 weeks. Angiogenesis-related proteins were detected in plasma and changes during everolimus treatment were analyzed. PTEN expression and PIK3CA mutations were correlated to disease control. Results: Two confirmed PR and eight SD were observed, resulting in a DCR of 27% at 8 weeks. Everolimus was well tolerated. Compared with patients with noncontrolled disease, we observed in patients with controlled disease a significant higher baseline level of angiopoietin-1 and a significant early plasma decrease in angiopoietin-1, endoglin,and platelet-derived growth factor-AB. PTEN loss was observed only in patients with PD. Conclusions: Everolimus showed clinical activity in advanced TCC. The profile of the plasma angiogenesis-related proteins suggested a role of the everolimus antiangiogenic properties in disease control. PTEN loss might be associated with everolimus resistance.

Background: Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer. Methods: Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m−2 plus irinotecan 250 mg m−2 (Day 1)) or 3-weekly DF (docetaxel 85 mg m−2 (Day 1) followed by 5-fluorouracil 750 mg m−2 per day as a continuous infusion (Days 1–5)). Results: A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3–4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively). Conclusion: Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.

Purpose: To demonstrate that an early increase in ctDNA plasmatic levels after 14 days may identify patients (pts) with advanced chemorefractory colorectal cancer (aCRC) unlikely to benefit from regorafenib. Experimental procedures: The RegARd-C prospective multicentric clinical trial (NCT01929616) collected archival tumor tissue and plasma samples at baseline (BL), 14 days (D14) and every 2 months after treatment initiation in aCRC pts (n=141). A targeted gene sequencing was performed on pts' tumor tissue to identify tumor-specific mutations using a panel of 47 genes commonly mutated in CRC. To monitor circulating tumor DNA (ctDNA) levels in plasma samples collected at BL and D14 via droplet digital PCR (Bio-Rad QX200 ddPCR system), we selected tumor-specific mutations based on their allelic frequency. Results: As foreseen, in 96 pts the most common mutated genes were APC (73%), TP53 (72%), KRAS (66%), and PI3KCA (23%). Among these pts, 24 (25%), 49 (51%), 18 (19%) and 5 (5%) had respectively one, two, three and four tumor-specific mutations followed via ddPCR. On average 2 (range 1-4) tumor-specific mutations were followed per patient. In total, 65 specific paired PrimePCRTM ddPCRTM Mutation Detection Assays were optimized following digital MIQE guidelines to assess ctDNA levels. As previously described1, ctDNA levels were assessed in terms of absolute values of mutated copies per mL of plasma to avoid bias in the mutated/mutated + wild-type copies ratio. We considered an increase in ctDNA level of at least 12% as significant2. Pts were separated according to the presence (n=53) or absence (n=43) of at least one increasing mutation between BL and D14. An increase of at least one tumor-specific mutation as compared to none is associated with a significantly worse clinical outcome with a median PFS of 1.3 months versus 3.0 months (HR 1.88, P=0.002, 95% CI 1.24-2.85) and a median OS of 3.9 months versus 8.5 months (HR 2.04, P Conclusion: Early (14 days) change in ctDNA levels under regorafenib therapy describes adequately the outcome of patients and may be used as a reliable tool for treatment personalization. Additionally, we confirmed the importance of using the absolute value of ctDNA instead of the mutated/total copies ratio usually reported in the literature for monitoring the outcome of a toxic treatment such as regorafenib. 1Kehagias P. et al. Oral presentation. LKI symposium, 2017; Leuven 2Whale AS. et al. Anal Chem. 2017 Citation Format: Pashalina Kehagias, Caroline Vandeputte, Lieveke Ameye, Hakim El Housni, Jean-François Laes, Amélie Deleporte, Karen Geboes, Thierry Delaunoit, Gauthier Demolin, Marc Peeters, Lionel D'Hondt, Jos Janssens, Javier Carrasco, Maria Gomez Galdon, Ghanem Ghanem, Pierre Heimann, Marianne Paesmans, Patrick Flamen, Alain Hendlisz. Circulating tumor DNA detects early response to regorafenib in advanced colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-221.

To evaluate the antitumor activity and toxicity of single-agent cetuximab in patients with recurrent high-grade glioma (HGG) after failure of surgery, radiation therapy, and chemotherapy.In this two-arm, open-label, phase II study patients were stratified according to their epidermal growth factor receptor (EGFR) gene amplification status. Cetuximab was administered intravenously at a dose of 400 mg/m(2) on week 1 followed by weekly dose of 250 mg/m(2). The primary end point for this study was the response rate in both study arms separately.Fifty-five eligible patients (28 with and 27 without EGFR amplification) tolerated cetuximab well. Three patients (5.5%) had a partial response and 16 patients (29.6%) had stable disease. The median time to progression was 1.9 months [95% confidence interval (CI) 1.6-2.2 months]. Whereas the progression-free survival (PFS) was6 months in the majority (n = 50/55) of patients, five patients (9.2%) had a PFS on cetuximab of9 months. Median overall survival was 5.0 months (95% CI 4.2-5.9 months). No significant correlation was found between response, survival and EGFR amplification.Cetuximab was well tolerated but had limited activity in this patient population with progressive HGG. A minority of patients may derive a more durable benefit but were not prospectively identified by EGFR gene copy number.

INTRODUCTION: We report here two cases of Agrobacterium radiobacter bacteremia. These cases were observed at the same institution over a short time period (3 months). CASE REPORTS: The first patient was a female cancer patient receiving third-line chemotherapy for ovarian carcinoma. When she developed bacteremia, she was neutropenic and had an indwelling catheter that was removed as part of the treatment. The second case was a geriatric patient admitted from home with bacteremia, clinical signs of septic shock, and concomitant acute cholecystitis. OUTCOME: Both patients responded promptly and completely to antibiotherapy. No recurrence was observed.

Dose-dense temozolomide schedules deplete O6-methylguanine methyltransferase and may overcome chemoresistance. This multicenter cohort study enrolled 19 patients (15 anaplastic astrocytoma, 4 anaplastic oligoastrocytoma) who received temozolomide (100 mg/m2/day for 21 consecutive days every 28-day cycle) at first recurrence, either until disease progression or 12 cycles. Six-month progression-free survival was 56%, comparing favorably with historic controls treated with the standard 5-day temozolomide schedule. Median survival was 12.9 months (95% CI: 3.7, 22 months). Among 15 evaluable patients, 2 had a complete or partial response, and 10 had stable disease. Grade 3 and 4 lymphopenia occurred in 53% and 47% of patients, respectively.

We report the case of a 62-year-old patient who developed a carcinomatous meningitis while on second-line chemotherapy for ovarian cancer. Cytologic analyses confirmed that carcinomatous cells of ovarian origin were present in cerebrospinal fluid. Carcinomatous meningitis is a very rare event in the natural history of ovarian carcinoma. We discuss the specificity of our case in the light of the literature. In addition, we present some relevant radiologic and pathologic documents illustrating this rare entity.

Circadian rhythms exist for hematopoiesis, but little is known about circadian variation of bone marrow engraftability and host “acceptability”. Using a B6.SJL to C57BL/6J congenic transplant model, we chose 3-times with light on: Hours After Light Onset (HALO) 4, 8, and 12 and 3-times with light off: HALO 16, 20, and 24. The mice were conditioned on a 12-h light/dark cycles. Recipient mice (100 cGy) received 40 million cells. We demonstrated a significant variation of bone marrow engraftability into bone marrow, spleen, and thymus when donor animals were subjected to changes in their light/dark cycles. Two statistically significant nadirs in all three organs were observed at HALO 8 and 24 in experiments carried out in July, while an identical set of experiments in February analyzing engraftment in marrow and spleen showed nadirs at HALO 8, but not at HALO 24. Marrow progenitors from the July experiments showed nadirs at HALO 12 and 24. The percentage of progenitors in S phase peaked at HALO 8 and 24. Interestingly, there were no changes in the ability of host to accept grafts with changes in the light/dark cycles of host animals. Circadian variations of bone marrow engraftability are important and should be considered in bone marrow transplant strategies. © 2004 Wiley-Liss, Inc.

Summary. Graft rejection and graft-versus-host disease are major problems in mismatched marrow transplants along with toxicity from standard myeloablative host treatments. We have established a tolerization model, using 1 Gy irradiation, which reduces stem cell capacity to

Bevacizumab (BEV) has demonstrated anti-tumor activity in patients with recurrent glioblastoma (rGB). Given the unmet need for active therapeutic options in rGB patients, a medical need program was initiated by the Belgian competent authorities. Between November 2010 and February 2013, a total of 313 patients with rGB initiated treatment with BEV administered at a dose of 10 mg/kg every 2 weeks. All patients had failed prior treatment with at least radiation therapy and temozolomide and the majority of patients (70 %) were treated with corticosteroids at baseline. Patients received a median of 6 BEV administrations (range 1-53). Overall, BEV was well tolerated. During BEV treatment the WHO-Performance Score (WHO-PS) improved in 59 patients (19 %) and stabilized for at least 6 weeks in an additional 139 (44 %) patients. Corticosteroid treatment could be stopped in 16 % or reduced in dose in 32 % of patients. The best objective tumor response rate using RANO criteria (investigator's assessment) was 3.5 % CR, 22 % PR, 38 % SD and 37 % PD. The median and 6-month PFS were 13 weeks (95 % CI 12.7-14) and 27.3 % (95 % CI 22.3-32.5), median and 6-month OS rates were 26 weeks (23-29) and 52 % (46.4-58.6), respectively. WHO-PS (0-1 vs. 2-3) and baseline steroid use were significantly correlated with PFS and OS. Our observations support the use of BEV as a monotherapy for patients with rGB who have no alternative treatment options. Optimal benefit from BEV treatment is likely to be obtained when treatment is initiated before the performance status deteriorates to two or less.

AIM: Treatment of locally advanced rectal cancer (LARC) includes preoperative radiation therapy with or without chemotherapy followed by radical surgery, but the clinical outcome is uncertain. A systemic review was carried out to determine the predictive value of (18)F-fluoro-2-deoxyglucose positron emission tomography ((18)FDG-PET) for assessing disease-free (DFS) and overall survival (OS) in LARC. METHOD: A literature search (PubMed/MEDLINE, EMBASE, Cochrane) up to January 2012 to identify full papers with sequential (18)FDG-PET and survival data, using indexing terms and free text words. The inclusion criteria were: a study of at least 10 patients, having sequential (18)FDG-PET imaging before and after adjuvant chemoradiation and a minimal follow-up of 24 months. Studies were selected by two of the authors. A meta-analysis was performed for DFS and OS using the hazard ratio (HR) as the primary outcome. RESULTS: Five eligible studies were identified including 330 patients (mean age 63 years, 64% men), in which PET-CT or PET imaging was used. The American Joint Committee on Cancer stage distribution was as follows: Stage I, 2%; Stage II, 44%; Stage III, 52%; Stage IV, 1%. The pooled HRs for complete metabolic response versus partial or no response were 0.39 (95% CI 0.18-0.86; P = 0.02) for OS and 0.70 (95% CI 0.16-3.14; P = 0.64) for DFS. The lack of significance for DFS might be explained by different follow-up characteristics. There was also clinical heterogeneity among the different studies. CONCLUSION: This systematic review indicates that complete metabolic response on sequential (18)FDG-PET data after preoperative chemoradiation of LARC is predictive of OS, but not of DFS.

We performed a dose-escalation study to investigate the safety of sorafenib in combination with docetaxel and prednisone in chemo-naive patients with metastatic castration-resistant prostate cancer (mCRPC). Six patients were included per dose level. Following docetaxel infusion on day 1 (75 mg/m2/q3 weeks), sorafenib was administered at 200 mg BID on days 2–19 (dose level 1), at 200 mg BID on days 1–21 (dose level 2), at 400 mg BID on days 2–19 (dose level 3), at 400 mg BID on days 1–21 (dose level 4). Maximal tolerated dose (MTD) was exceeded if ≥2 patients experienced dose-limiting toxicities (DLT) during cycle 1. The recommended phase 2 dose for sorafenib was defined as one dose level below MTD. If MTD was not reached, the highest feasible dose would be selected to treat an expanded cohort to confirm safety. Two DLTs were observed during sorafenib dose-escalation consisting of grade 4 febrile neutropenia (dose level 2) and grade 3 hand-foot syndrome (HFS) (dose level 3). Our pharmacokinetic results showed an increased exposure to docetaxel across all dose levels during sorafenib comedication. The main grade ≥3 toxicities were neutropenia (35 %), HFS (27 %), and febrile neutropenia (19 %). The prostate-specific antigen (PSA) response rate was 74 %. Median overall survival was 25.2 months. Three-weekly docetaxel and prednisone could be combined with sorafenib at 400 mg BID on days 1–21 without reaching MTD. However, we observed a pharmacokinetic interaction between sorafenib and docetaxel, associated with significant toxicities, raising concerns about the safety of this combination in mCRPC.

Purpose To assess the efficacy and toxicity of the addition of estramustine to docetaxel (D) for the treatment of metastatic hormone-refractory prostate cancer. Patients and Methods One hundred fifty patients were randomly assigned to D alone (35 mg/m2 on days 2 and 9, every 3 weeks) or D in combination with estramustine (D/E; 280 mg orally three times a day on days 1 to 5 and 8 to 12, every 3 weeks). All patients received prednisone (10 mg/d). The primary end point was prostate-specific antigen (PSA) response rate, which was defined as a decrease in PSA ≥ 50% from baseline. The study was powered to test the hypothesis that D/E would improve the PSA response rate by 25%. Results The PSA response rate was not statistically different between the two groups. PSA of less than 4 ng/mL occurred in 29 (41%) of 71 patients receiving D/E and in 17 (25%) of 69 patients receiving D (P = .05). No significant differences were found for median time to PSA progression (D/E, 6.9 months; D, 7.3 months) or median overall survival time (D/E, 19.3 months; D, 21 months). More patients had at least one grade 3 or 4 toxicity with D/E (45%) compared with D (21%; P = .005), mainly as a result of grade 3 or 4 GI toxicity (P = .05). Serious adverse events were more frequent with D/E (n = 20) than with D (n = 9; P = .04). Conclusion The addition of estramustine to weekly D does not provide any clinically relevant advantage. Both regimens are well tolerated, although the toxicity profile favors D without estramustine.

To investigate the correlation between O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation and benefit from temozolomide in patients with recurrent high-grade glioma.A real-time, quantitative, methylation-specific PCR assay was performed on archival tissue blocks from patients treated with temozolomide at the first recurrence.A subgroup of 38 patients who were chemotherapy-naive at recurrence was analysed (22 glioblastoma, 12 anaplastic astrocytoma [AA] and 4 anaplastic oligoastrocytoma [AOA]); none had 1p/19q loss. Among 10 (26%) patients with a hypermethylated MGMT promoter, none experienced disease progression within the first two treatment cycles compared with 12 of 28 (43%) patients with an unmethylated promoter (p=0.016). By Cox multivariate analysis, tumour grade and MGMT promoter methylation correlated with time to progression (p0.05); MGMT promoter methylation correlated with superior overall survival in AA/AOA but not in glioblastoma.MGMT promoter methylation predicted a survival benefit in patients with 1p/19q intact AA/AOA treated with temozolomide at recurrence.

e16057 Background: To assess efficacy and safety of abiraterone acetate (AA) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel who started treatment during the AA compassionate use program (January 2011 - July 2012). Methods: We retrospectively analyzed records from 368 patients from 23 different Belgian hospitals. All patients had mCRPC, received prior chemotherapy and started AA at the standard dose of 1000mg per day with 10mg prednisone or equivalent. Principal outcomes measured were prostate-specific antigen (PSA) response (defined as a decrease ≥ 50%), time to PSA progression (defined as an increase > 50% over PSA nadir in case of PSA response or > 25% in the absence of PSA response), time to radiographic progression (according to Response Evaluation Criteria In Solid Tumors 1.1 criteria), overall and cancer-specific survival and occurrence of adverse events (according to Common Terminology Criteria for Adverse Events v4.03). Kaplan-Meier stati...

TPS795 Background: Even if the use of targeted therapies combined with chemotherapy has demonstrated increase response rate and survival benefit in non resectable metastatic colorectal cancer (mCRC), the administration of these combinations in frontline resectable disease is source of debate and optimal association is still unclear. Based on a retrospective analysis, we previously reported thatthe chemotherapy partner combined with VEGF or EGFR inhibitors influenced pathological responses (pR) on the resected colorectal cancer metastases (CRCM) with a significant advantage for oxaliplatin with anti-VEGF or irinotecan with anti-EGFR combinations. We aimed to design 2 parallel studies (BEV-ONCO, CET-ONCO) to prospectively precise optimal combination between oxaliplatin and irinotecan with bevacizumab or cetuximab before CRCM resection. Methods: The 2 studies are open label randomized multi-centric trials and concern mCRC patients with resectable disease in whom a preoperative treatment is considered. The primary objective is to assess the CRCM pR rate according the Tumor Regression Grade classification (Rubbia-Brandt) after allocated preoperative treatment (bevacizumab combined with FOLFOX vs. FOLFIRI without consideration of RAS/BRAF for BEV-ONCO trial (EUDRACT 2012-005376-34) and cetuximab associated with FOLFOX or FOLFIRI only for RAS/BRAF wild type tumor for CET-ONCO trial (EUDRACT 2012-005249-19)). According investigator’s choice, patient will received 3 to 6 treatment cycles before CRCM resection. Patient’s survival, safety, surgical complications and treatment associated liver-toxicity are secondary end-points. Up to 60 patients (30 per treatment group) will be randomised in each study (power: 80%, type I error of 5% to detect a difference in proportion of pR rate between FOLFOX or FOLFIRI association of 0.40). Formal comparison will not be done across studies. Translational research projects are ongoing (CRCM immune response, tumour specific genetic rearrangements as new specific biomarkers). Clinical trial information: NCT01858649 (BEV-ONCO); NCT01858662 (CET-ONCO). Clinical trial information: NCT01858649 (BEVONCO) NCT01858662 (CETONCO).

This study was designed to establish a direct homing assay using purified lineage-negative Sca-1-positive (Lin(-) Sca(+)) murine bone marrow cells and to evaluate the effects of cytokines on homing. C57BL/6 Lin(-) Sca(+) marrow stem cells were labeled with 5-(and 6)-carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) and then injected by tail vein into untreated C57BL/6 mice. Marrow was harvested at various times after cell infusion and analyzed on a high-speed MoFlo cell sorter for fluorescent positive events, using a large event analysis, with at least 16 million total events analyzed. We have shown that homing of Lin(-) Sca(+) cells plateaus by 1 h, and at 3 h post-infusion is linear between 50,000 and 1,000,000 infused cells. This forms a base for a homing assay in which 250,000 CFDA-SE labeled Lin(-) Sca(+) marrow cells are infused and then recovered from marrow 3 h later, followed by a large-event fluorescence-activated cell sorting (FACS) analysis. We found that 7.45-9.32% of infused cells homed and that homing of stem cells cultured for 48 h in interleukin-3 (IL-3), IL-6, IL-11, and steel factor cultured cells was defective when compared to noncultured cells. Exposure of marrow stem cells to IL-3, IL-6, IL-11, and steel factor induces a stem cell homing defect, which probably underlies the engraftment defect previously characterized under these conditions.

BACKGROUND: It is not known whether increasing the dose of filgrastim after mobilizing chemotherapy improves collection of peripheral blood progenitor cells (PBPC) and leads to faster hematopoietic engraftment after autologous transplantation. STUDY DESIGN AND METHODS: A randomized, open-label, multicenter trial was carried out in patients with breast cancer, multiple myeloma, and lymphoma, in which patients were randomized to receive 5 or 10 microg per kg per day of filgrastim after standard chemotherapy to mobilize PBPCs. After high-dose chemotherapy, the components from the first two leukapheresis procedures were returned, and all patients received 5 microg per kg day of filgrastim after transplantation. RESULTS: A total of 131 patients were randomized, of whom 128 were mobilized (Group A, 5 microg/kg, n = 66; Group B, 10 microg/kg, n = 62) and 112 were transplanted. Only six patients were not transplanted because of insufficient CD34+ cell numbers. The median number of CD34+ cells collected in the first two leukapheresis procedures tended to be higher in Group B than in Group A (12.0 vs. 7.2 x 10(6)/kg, NS), but after transplantation there was no significant difference in median times to platelet (9 days in both groups) or neutrophil (8 days in both groups) engraftment or the number of platelet transfusions (three in both groups). A subsequent subgroup analysis separating patients transplanted after first- or second-line chemotherapy also showed no measurable impact of filgrastim dose on the median CD34+ cell yield or on platelet engraftment in either subgroup. CONCLUSION: PBPC mobilization with chemotherapy and 5 microg per kg of filgrastim is very efficient, and 10 microg per kg of filgrastim does not provide additional clinical benefit.

Minimal myeloablative approaches are now being widely applied in the treatment of different hematological malignancies. One hundred cGy whole-body irradiation is a stem-cell-toxic, relatively non-myelotoxic treatment that allows for relatively high levels of donor chimerism. 5-Fluorouracil (5-FU) treatment leads to a relative concentration of high proliferative potential-colony-forming cell (HPP-CFC) and is an approach that has been used to induce in vivo progenitor/stem cell cycling to facilitate retroviral integration in gene therapy approaches. We have now evaluated the capacity of marrow harvested 1, 2, 6, or 12 days after 5-FU treatment (150 mg/kg) to engraft in 100 cGy-treated female BALB/c mice. Engraftment was assessed at 3, 10, and 24 weeks. A rapid induction of an engraftment defect occurred 1 day post 5-FU and persisted through day 6 with a recovery by day 12. To evaluate cell cycle status of normal and 5-FU-treated marrow cells, male donors received hydroxyurea (900 mg/kg i.v.) or phosphate-buffered saline (PBS), 2 h prior to marrow harvest and transplantation into submyeloablated female recipients. Engraftment levels were similar for hydroxyurea-treated mice and controls. Thus, these studies show transiently defective engraftment of 5-FU-treated marrow into submyeloablated hosts, which may be related to the cell cycle status of the stem cells.

385 Background: Adjuvant chemotherapy (CT) improves stage III CC outcome but is not effective for all patients (pts). PePiTA’s main hypothesis is that absence of metabolic response (MR) of the primary tumor after 1 preop CT course predicts absence of benefit from adjuvant CT (at 3-year DFS). This strategy's aim is to spare pts from useless toxicities, improve healthcare resource allocation, and guide translational research. This interim analysis was performed for safety and feasibility of MR assessment (MRA). Methods: Pts ≥ 18 years, with PS ≤ 1, diagnosed with CC considered for curative resection are eligible, after signed consent. Baseline PET is repeated after 1 CT cycle, followed by surgery. PET quality insurance and MRA are performed centrally and the result is blinded for investigators. Results: From 2010 to 2013, 114 pts—M/F (55%/45%), median age 66 (26-81), ECOG 0/1(92%/8%)—were included in 15 Belgian centers. 11 pts were excluded from analysis: 2 hyperglycemia at baseline PET; 2 withdrew consent; 6 PET-revealed stage IV CC; and 1 second cancer. Preop CT was associated with 5% grade (gr) 3-4 neutropenia, 1% gr 3 diarrhea, 1% gr 3 hypokaliemia, 1% peritonitis and 1% gr 3 thromboembolic events. Colectomies were performed in all pts after a median of 20 days (interquartile interval 18-21): 32 right (31%), 69 left (67%), and 2 procedures not detailed. Pathology showed stages 0 (1%), I (13%), II (34%), III (47%), IV (7%), without lymph node downstaging. Postoperative morbidity is 9% (95%CI 5-16%) and includes fistulas (4%), transient ischemic attack (1%), ileus (2%), and evisceration (1%), but no death. Technical or methodological reasons prevented MRA in 19/103 pts. Median SUVmax was 14.4 (4.9-47.8) at baseline, and 10.9 (0-39.3) on day 14. 2 pts presented with complete MR. For the others, median delta SUVmax was -22% (-60 to +31%). MR was observed in 60% of pts, and was absent in 40%, with equal distribution for stages II and III (p = 1.00). Conclusions: 1 course of CT is feasible before curative surgery for CC, without inducing excessive toxicity, delay or surgical morbidity. MRA indicated metabolic signs of chemoresistance in 40% of the primary tumors. Clinical trial information: NCT00994864.

The donor stem cell phenotype and host microenvironment determine the outcome of a stem cell transplant. In a series of transplant studies in syngeneic male to female or congenic Ly5.1/Ly5.2 models in which hosts have received no or minimal irradiation (100 cGy), evidence overwhelmingly supports the concept that syngeneic engraftment is determined by stem cell competition. These approaches can be extended to H-2 mismatched allogeneic mouse combination when antigen pre-exposure and CD40-CD40 ligand antibody blockage are employed. A human trial in patients with resistant neoplasia infusing pheresed blood with 10(8) CD3 cells/kg showed that tumor responses and complete chimerism occur with very low levels of CD34+ cells/kg and that the extent of previous treatment is a critical factor in determining chimerism. A major feature of transplants is the phenotype of the donor stem cell. This phenotype shows dramatic reversible plasticity involving differentiation, adhesion protein expression, and engraftment with cytokine-induced cell-cycle transit. Homing is probably also plastic. Marked fluctuations in engraftment capacity are also seen at different points in marrow circadian rhythm.

We evaluated the engraftment and the cell cycle status of marrow cells at various times after 5-fluorouracil (5-FU) administration. 5-FU (150 mg/kg) was given to donor male BALB/c mice at 1, 2, 6, or 12 days prior to marrow harvest. The donor cells were then assessed in host nonmyeloablated female mice. Bone marrow engraftment of marrow treated with 5-FU was evaluated and compared to marrow treated with diluent (phosphate-buffered saline) at 3 and 10 weeks after marrow infusion. Our data show a rapid induction of an engraftment defect 1 day after 5-FU, persistence of this defect through day 6, and a recovery by day 12. Experiments using hydroxyurea (which selectively kills cells in the S phase) to determine the cell cycle status indicated that cells that engrafted in post-5-FU marrow were noncycling at days 1, 2, and 12 but cycling at day 6. Post-5-FU bone marrow was also analyzed in vitro by colony assays and its cycling status determined by 3H-thymidine suicide assay. High-proliferative-potential colony-forming cells (HPP-CFCs) and low-proliferative-potential colony-forming cells (LPP-CFCs) decreased rapidly 1 day after 5-FU, with a nadir observed at day 6 for HPP-CFCs and day 2 for LPP-CFCs. By day 12, LPP-CFCs showed a total recovery, but HPP-CFCs were still defective. Significant numbers of HPP-CFCs were cycling, mostly at days 6 and 8 after 5-FU, whereas LPP-CFCs appeared quiescent except at day 2. These results emphasize the importance of timing if post-5-FU marrow is used for gene therapy or marrow transplantation.

Some heavily pretreated cancer patients fail to mobilize enough peripheral blood stem cells (PBSC) after stimulation with chemotherapy and hematopoietic growth factors. For these patients the best way to obtain an adequate PBSC collection is unknown. Here we report 6 heavily pretreated cancer patients who failed to mobilize sufficient PBSC after stimulation with chemotherapy and G-CSF 5 microg/kg/day. In these cases, we used G-CSF 10 microg/kg/day alone for six days at least 3 weeks after the last chemotherapy. After three consecutive leukaphereses starting on day 5, five patients had adequate PBSC collections. With 6 days of G-CSF 10 microg/kg/day alone, 2.8 x 10(6) (+/- 1) CD34+ cells/kg were collected. This was significantly higher than the number of CD34+ cells/kg collected after chemotherapy and G-CSF 5 microg/kg 0.3 x 10(6) (+/- 0.1) [P = 0.05]. Four patients received high-dose chemotherapy with PBSC support. Hematologic recovery observed in these patients was as expected. In conclusion, G-CSF 10 microg/kg alone can mobilize progenitor cells into peripheral blood when previous mobilization with chemotherapy and G-CSF 5 microg/kg fails.

TPS134 Background: The overall survival (OS) of newly diagnosed glioblastoma (GB) patients (pts) treated with RT and TMZ is correlated with the methylation status of the MGMT-promoter. Pts with an ...

Numerous studies have demonstrated the influence of circadian rhythm on the hematopoietic system but little is known about variation of BM engraftability throughout the day. We transplanted 40 × 10 6 Ly5.1 (B6.SJL) BM cells into submyeloablated (100 cGY) Ly5.2 (C57BL/6J) recipients. Donors were kept isolated in 2 custom built cabinets in order to ensure 12 hours of light and 12 hours of dark. Recipients were also synchronized in order to receive the transplant consistently at Circadian Time (CT) 8 (2 pm). We had 15 donors and 15 recipients for each CT. For transplant, marrow was pooled into three groups of five. Percent (± SD) engraftment was determined by the ratio Ly5.2/(Ly5.1 + Ly5.2). There was a significant fluctuation (p These in vivo observations were complemented by in vitro analysis of donor BM. Colony-assays (HPP-CFC), thymidine suicide tests (percentage of cycling cells), and lineage analysis were performed. Significant asynchronous fluctuations of HPP-CFC numbers were seen while proliferation varied inversely with engraftment. These data provide statistically significant evidence of circadian variations of BM engraftability and form a base for further studies of stem cell chronobiology.

5153 Background: Docetaxel (D)-prednisone (P) is the standard regimen for metastatic castrate-resistant prostate cancer (mCRPC). Sorafenib (S) is a dual-action kinase inhibitor that blocks cell proliferation and angiogenesis with antitumor activity in CRPC. The objectives were dose limiting toxicities (DLTs)/recommended dose (RD) of S in combination with D-P, pharmacokinetics (PK), and safety at the RD in an expanded cohort. Methods: 6 pts were enrolled per dose level (DL). All pts received D 75 mg/m2/3 wks in 6 chemotherapy cycles and P 10 mg/d. S dose escalation included 4 DL. DL 1: S 200 mg bid from day 3 to 19 of each chemotherapy cycle. DL 2: S 200 mg bid started at day 3 of the 1st cycle and continued without interruption through the cycles. DL 3: S 400 mg bid from day 3 to 19 of each cycle. DL 4: S 400 mg bid started at day 3 of the 1st cycle without interruption through the cycles. DLTs were determined during the first cycle. Results: 24 chemo-naive mCRPC pts (median age 68) were included in the dose-escalation study. PK analysis showed that mean Cmax and AUC of D were increased at cycle 2 in cohort 2, 3, and 4 indicating a PK interaction dependent on the exposure to S. For the 24 pts, the main Gr 3–4 toxicities (N pts) were febrile neutropenia (8), uncomplicated neutropenia (5), and hand-foot syndrome (4). No DLT was found. PSA response (> 50% in PSA decrease) was recorded in 15 out of 20 pts. Conclusions: The RD of S in combination with D is 400 mg bid continuously. PK analysis revealed an interaction between D and S that may explain the high rate of febrile neutropenia and Gr4 neutropenia. 14 pts were included in an expanded cohort to further explore the safety of this regimen. Updated data will be presented. [Table: see text] No significant financial relationships to disclose.