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This supplementary figure shows the gating strategy to analyze T cell transendothelial migration (A), and the migration of CD4+ (B) and CD8+ T cells (C) after endothelial activation.

T cell–mediated immunity is a major component of antitumor immunity. In order to be efficient, effector T cells must leave the circulation and enter into the tumor tissue. Regulatory T cells (Treg) from gastric cancer patients, but not from healthy volunteers, potently inhibit migration of conventional T cells through activated endothelium. In this study, we compared T cells from colon cancer patients and healthy donors to determine the mechanisms used by Tregs from cancer patients to inhibit conventional T-cell migration. Our results showed that circulating Tregs from cancer patients expressed high levels of CD39, an ectoenzyme mediating hydrolysis of ATP to AMP, as a rate-determining first step in the generation of immunosuppressive adenosine. Tumor-associated Tregs expressed even more CD39, and we therefore examined the importance of adenosine in Treg-mediated inhibition of T-cell transendothelial migration in vitro. Exogenous adenosine significantly reduced migration of conventional T cells from healthy volunteers, and blocking either adenosine receptors or CD39 enzymatic activity during transmigration restored the ability of conventional T cells from cancer patients to migrate. Adenosine did not directly affect T cells or endothelial cells, but reduced the ability of monocytes to activate the endothelium. Taken together, our results indicate that Treg-derived adenosine acts on monocytes and contributes to reduced transendothelial migration of effector T cells into tumors. This effect of Tregs is specific for cancer patients, and our results indicate that Tregs may affect not only T-cell effector functions but also their migration into tumors. Cancer Immunol Res; 4(3); 183–93. ©2016 AACR.

The combination of 5-fluorouracil (5-FU) and leucovorin (LV) forms the chemotherapy backbone for patients with colorectal cancer. However, the LV administration is often standardized and not based on robust scientific data. To address these issues, a randomized pharmacokinetics study was performed in patients with colon cancer. Thirty patients were enrolled, receiving 60, 200 or 500 mg/m2 LV as a single two-hour infusion. Blood, tumor, mucosa, and resection margin biopsies were collected. Folate concentrations were analyzed with LC-MS/MS and gene expression with qPCR. Data from a previous study where patients received LV as bolus injections were used as comparison. Saturation of methylenetetrahydrofolate (MeTHF) and tetrahydrofolate (THF) levels was seen after two-hour infusion and polyglutamated MeTHF + THF levels in tumors decreased with increasing LV dosage. The decrease was associated with decreased FPGS and increased GGH expression, which was not observed after LV bolus injection. In the bolus group, results indicate activation of a metabolic switch possibly promoting TYMS inhibition in response to 5-FU. Different metabolic mechanisms appear to be induced when LV is administered as infusion and bolus injection. Since maximal inhibition of TYMS by the 5-FU metabolite 5-fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP) requires excess polyglutamated MeTHF, the results point in favor of the bolus regimen.

Background Intratumoral regulatory T cells (Treg) in colon cancer are a heterogeneous cell population, with potential impact on patient outcome. Generally, a high Treg infiltration has been correlated to a worse patient outcome, but it is still unclear how the composition of different Treg subsets affects patient relapse and survival. In this study, we used mass and flow cytometry to characterize Treg in colon tumors and corresponding unaffected tissue, followed by a correlation to clinical parameters and patient outcome. Results Using mass cytometry, we defined 13 clusters of intestinal Treg, three of which were enriched in the tumors. The two most enriched clusters were defined by their expression of the proliferation marker Ki67 and CD56, respectively. The Treg accumulating in the tumors expressed inducible T-cell co-stimulator (ICOS), OX-40, and CD39, indicating that they were effector Treg (eTreg). Intratumoral CD39+ Treg also had a higher expression of Foxp3, suggesting a higher suppressive activity, and we subsequently used CD39 as a marker for eTreg. Our further studies showed that colon tumors can be divided into two tumor groups, based on the proportion of CD39+ putative eTreg in the tumors. This property was independent of both tumor microsatellite status and tumor stage, which are important factors in predicting cancer disease progression. In a prospective study of forty-four colon cancer patients, we also showed that patients with a high CD39 expression on tumor-infiltrating Treg have a tendency towards a less favorable patient outcome in terms of cumulative cancer-specific survival. Conclusions This study uncovers novel subsets of tumor-infiltrating Treg in colon cancer, and suggests that CD39 may be a potential therapeutic target in patients with microsatellite stable colon tumors, which are usually refractory to checkpoint blockade therapy.

Purpose The aim was to explore the correlation between increasing doses of [6R]-5,10-methylenetetrahydrofolate (arfolitixorin) and plasma concentrations of deoxyuridine (dUr) in patients with metastatic colorectal cancer (mCRC), subjected to 5-fluorouracil (5-FU)-based chemotherapy. The aim was further to investigate the possibility to predict toxicity and clinical response during treatment using gender, age, and plasma dUr as explanatory variables. Methods Thirty-three patients from the ISO-CC-005 phase I/IIa study, which investigated safety and tolerability of arfolitixorin at four dose levels, were included. Toxicity and clinical response were evaluated after 4 cycles of chemotherapy. Plasma dUr was quantified before (0 h) and 24 h after 5-FU administration at the first (C1) and fourth (C4) cycle using LC–MS/MS. Fit modelling was used to predict toxicity and clinical response. Results The dUr levels increased with increasing arfolitixorin dose. Females had higher total and haematological toxicity scores (p = 0.0004 and 0.0089, respectively), and needed dose reduction more often than males (p = 0.012). Fit modeling showed that gender and the dUr levels at C1-0 h and C4-24 h predicted total toxicity (p = 0.0011), whereas dUr C4-0 h alone was associated with gastrointestinal toxicity (p = 0.026). Haematological toxicity was predicted by gender and age (p = 0.0071). The haematological toxicity score in combination with the dUr levels at C1-24 h and C4-24 h predicted early clinical response (p = 0.018). Conclusion The dUr level before and during administration of 5-FU and arfolitixorin was predictive for toxicity and early clinical response and could be a potential surrogate marker for thymidylate synthase inhibition in patients with mCRC. Trial registration NCT02244632, first posted on ClinicalTrials.gov on September 19, 2014

BACKGROUND: Brain tumours are the most common solid tumours in childhood. Half of these tumours occur in the posterior fossa, where surgical removal is complicated by the risk of cerebellar mutism syndrome, of which postoperative speech impairment (POSI) is a cardinal symptom, in up to 25% of patients. The surgical approach to midline tumours, mostly undertaken by transvermian or telovelar routes, has been proposed to influence the risk of POSI. We aimed to investigate the risk of developing POSI, the time course of its resolution, and its association with surgical approach and other clinical factors. METHODS: In this observational prospective multicentre cohort study, we included children (aged

Background: Advances in therapy have improved outcomes in multiple myeloma (MM), but enhancement in overall survival (OS) has resulted in patients living with the burden of symptoms and complications of relapsed/refractory MM (RRMM) and prior lines of therapy (Vogl et al. Leuk Lymphoma. 2018;59:398; Kumar et al. Leukemia. 2017;31:2443). Elderly patients represent a particularly difficult-to-treat population with RRMM due to the additional presence of comorbidities, reduced fitness level, and treatment with concomitant medications (Larocca et al. Leukemia. 2018;32:1697). There is an unmet need for efficacious and convenient treatment options with manageable side effects to optimize tolerability for elderly patients with RRMM. Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. In the phase 2 HORIZON study (OP-106; NCT02963493), melflufen plus dexamethasone (dex) demonstrated encouraging efficacy and a clinically manageable safety profile in patients with heavily pretreated RRMM (Richardson et al. EHA 2020. Abs. EP945). This analysis examines the efficacy and safety of melflufen plus dex in the subset of patients aged ≥75 years in the HORIZON study. Methods: Patients with RRMM must have received ≥2 prior lines of therapy, including an IMiD and a proteasome inhibitor, and been refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. Pts received melflufen 40 mg intravenously on day 1 and dex 40 mg per week (20 mg in patients aged ≥75 years) during each 28-day treatment cycle until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR; ≥ partial response [PR]; investigator-assessed per International Myeloma Working Group criteria). Secondary endpoints included progression-free survival (PFS), OS, duration of response (DOR), and safety. An analysis was conducted in the intention-to-treat population for patients aged ≥75 years. Results: As of the data cutoff date (January 14, 2020), 157 patients were enrolled and treated; 25 (16%) were aged ≥75 years. Baseline characteristics for older patients were generally similar to that of the overall population and were indicative of a heavily pretreated population with a poor prognosis. Among patients aged ≥75 years, the median age was 77 years (range, 75-86); 32% had International Staging System stage 3; and 24% had extramedullary disease. Patients had received a median of 5 prior lines of therapy (range, 2-8), and 76% had triple-class-refractory MM. Efficacy results were consistent with those of the overall population and were not affected negatively by advanced patient age. ORR was 32% and 29% in patients aged ≥75 years and in the overall population, respectively (Table). In responding patients, median DOR was not reached in patients aged ≥75 years and was 5.5 months in the overall population. In patients aged ≥75 years and the overall population, median PFS was 5.6 months and 4.2 months, respectively, and median OS was 13.5 months and 11.6 months, respectively. In patients aged ≥75 years and the overall population, respectively, grade 3/4 AEs occurred in 96% and 89% of patients, most commonly neutropenia (44% and 53%), white blood cell count decrease (44% and 26%), thrombocytopenia (40% and 57%), and anemia (40% and 43%); the most common nonhematologic grade 3/4 AEs were pneumonia (20% and 10%), hypertension (12% and 2%), febrile neutropenia (12% and 6%), and hypophosphatemia (12% and 5%). Serious AEs occurred in 40% of patients aged ≥75 years and in 49% of the overall population, most commonly, pneumonia (16% [4 events] and 9% [14 events]); all other serious AEs in patients aged ≥75 years were observed in 1 patient each (4%). There were no treatment-related deaths. Conclusion: Melflufen, once monthly infusion, plus weekly dex demonstrated clinically meaningful efficacy and a manageable safety profile in older patients with heavily pretreated RRMM. In patients aged ≥75 years, treatment resulted in durable responses, with a safety profile consistent with that in previous reports. Further study is warranted to confirm these results suggesting that melflufen may be an efficacious, convenient, and tolerable therapy for elderly patients with RRMM who have limited treatment options. Disclosures Larocca: Amgen: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Oriol:Janssen: Consultancy; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees. Blade Creixenti:Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Cavo:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rodríguez-Otero:Janssen, BMS: Other: Travel, accommodations, expenses; BMS, Janssen, Amgen: Honoraria; Janssen, BMS, AbbVie, Sanofi, GSK, Oncopeptides, Kite, Amgen: Consultancy, Honoraria; Celgene-BMS: Consultancy, Honoraria; Mundipharma: Research Funding. Leleu:Amgen: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Oncopeptide: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; Karyopharm: Honoraria; GSK: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; BMS-celgene: Honoraria. Nadeem:Adaptive: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hassoun:Celgene: Research Funding; Takeda: Research Funding; Novartis: Consultancy. Touzeau:Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Amor:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Maisel:Takeda: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Texas Oncology: Current Employment; Karyopharm: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Texas Oncology: Current Employment; Celgene: Honoraria, Speakers Bureau. Mazumder:Celgene: Honoraria, Speakers Bureau; The Oncology Institute: Current Employment; Amgen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Raptis:INTEGRA: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; UPMC: Current Employment. Puig:JANSSEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; THE BINDING SITE: Consultancy, Honoraria; AMGEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; BRISTOL-MYERS SQUIBB: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; CELGENE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding. Thuresson:Statisticon: Current Employment; Oncopeptides: Consultancy, Current equity holder in publicly-traded company. Harmenberg:Oncopeptides AB: Consultancy, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Ultupharma AB: Current equity holder in private company; Medivir AB: Current equity holder in publicly-traded company. Gustavsson:PiezoMotor AB: Current equity holder in publicly-traded company; Sangus Jazz AB: Current equity holder in private company; Bristol-Myers Squibb: Divested equity in a private or publicly-traded company in the past 24 months; Celgene: Divested equity in a private or publicly-traded company in the past 24 months; XSpray AB: Divested equity in a private or publicly-traded company in the past 24 months; Vinnova: Honoraria; Episurf AB: Current equity holder in publicly-traded company; Nanexa AB: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides AB: Current Employment, Current equity holder in publicly-traded company. Mateos:GlaxoSmithKline: Honoraria; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This is a phase 2 investigational study of melflufen in RRMM.

Background: In patients with relapsed/refractory multiple myeloma (RRMM), 29%-59% have high-risk (HR) cytogenetic abnormalities that are associated with poor treatment outcomes (Kumar et al. Leukemia. 2017;31:2443; Gandhi et al. Leukemia. 2019;33:2266). Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. Melflufen plus dexamethasone (dex) showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated and poor-risk RRMM in the phase 2 HORIZON study (OP-106; NCT02963493; Richardson et al. EHA 2020. Abs. EP945). The overall response rate (ORR) was 29%, median progression-free survival (PFS) was 4.2 months, and median overall survival (OS) was 11.6 months. The most common nonhematologic grade 3/4 adverse event (AE) was pneumonia (10%). This is an analysis of the cytogenetic profile and a comparison of the efficacy for patients with and without HR cytogenetic abnormalities in the HORIZON study. Methods: Patients with RRMM had received ≥2 lines of prior therapy, including an IMiD and a proteasome inhibitor, and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. Patients received melflufen 40 mg (intravenously on day 1 of each 28-day cycle) and dex 40 mg/wk until progressive disease or unacceptable toxicity. The primary endpoint was ORR (≥ partial response [PR]; investigator-assessed per International Myeloma Working Group criteria); secondary endpoints included PFS, OS, duration of response (DOR), and safety. At screening, cytogenetics were evaluated using plasma cells from bone marrow aspirate by interphase fluorescence in situ hybridization and by conventional karyotyping. HR cytogenetic abnormalities were classified by the presence of t(4;14), t(14;16), t(14;20), del(17/17p), or gain(1q) (Sonneveld et al. Blood. 2016;127:2955). Results: Of the 157 patients enrolled and treated (data cutoff date, January 14, 2020), 59 (38%) had HR cytogenetic abnormalities at screening. Cytogenetic status was missing/unknown in 31 patients (20%). Among patients with HR cytogenetics, gain(1q) was seen in 41 (69%), del(17p) in 31%, t(4:14) in 31%, t(14:16) in 7%, and t(14:20) in none. Although baseline characteristics were generally similar between patients with and without HR cytogenetics (Table), fewer patients with HR cytogenetics had triple-class-refractory MM (69%) than those without HR cytogenetics (80%). The ORR (95% CI) was 20% (11-33) in patients with HR cytogenetics and 35% (25-45) in patients without HR cytogenetics. Among responding patients with HR cytogenetics (n=12), 4 achieved a very good PR and 8 a PR, with a median DOR of 6.7 months (95% CI, 3.0-not evaluable). Median DOR was 5.1 months (95% CI, 3.9-7.5) in patients without HR cytogenetics (n=34). Median PFS was 3.1 months (95% CI, 2.1-5.4) and 4.4 months (95% CI, 3.8-5.1), respectively, and OS was 11.5 months (95% CI, 8.5-13.6) and 13.2 months (95% CI, 8.1-17.6), respectively, in patients with and without HR cytogenetics. Among patients with HR cytogenetics, the ORR was 24% (95% CI, 11-40) in patients with 1 HR cytogenetic abnormality (n=38) and 14% (95% CI, 3-36) in patients with ≥2 HR cytogenetic abnormalities (n=21). Median PFS was 2.9 months (95% CI, 1.9-7.6) and 4.4 months (95% CI, 1.9-6.5), and OS was 11.6 months (95% CI, 7.7-21.1) and 11.5 months (95% CI, 4.5-13.9) in patients with 1 and ≥2 HR cytogenetic abnormalities, respectively. In patients with HR cytogenetics (n=59) and the overall population (N=157), grade 3/4 AEs were reported in 92% and 89%, respectively; the most common grade 3/4 AEs were thrombocytopenia (51% and 57%), neutropenia (47% and 53%), and anemia (36% and 43%); the most common nonhematologic grade 3/4 AE was pneumonia (17% and 10%). Serious AEs occurred in 54% of patients with HR cytogenetics and in 49% of patients in the overall population, most commonly pneumonia (17% and 9%, respectively). Conclusions: In the HORIZON study, melflufen plus dex also showed efficacy in patients with HR cytogenetics. The safety profile of melflufen plus dex in patients with HR cytogenetics was consistent with that of the overall population. Taken together, these data support further evaluation of melflufen plus dex in RRMM with HR cytogenetics. Disclosures Mateos: GlaxoSmithKline: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Larocca:Amgen: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Blade Creixenti:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Cavo:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rodríguez-Otero:Kite: Consultancy; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy; Abbvie: Consultancy; Medscape: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene/Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company; Oncopeptides: Consultancy. Leleu:BMS-celgene: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; GSK: Honoraria; AbbVie: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Merck: Honoraria; Novartis: Honoraria. Nadeem:Adaptive: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Hassoun:Takeda: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Touzeau:Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Sanofi: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Amor:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Maisel:Texas Oncology: Current Employment; Texas Oncology: Current Employment; Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau. Mazumder:Takeda: Honoraria, Speakers Bureau; The Oncology Institute: Current Employment; Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Raptis:INTEGRA: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; UPMC: Current Employment. Puig:CELGENE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; AMGEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; JANSSEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; THE BINDING SITE: Consultancy, Honoraria; TAKEDA: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; BRISTOL-MYERS SQUIBB: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau. Harmenberg:Oncopeptides AB: Consultancy, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Medivir AB: Current equity holder in publicly-traded company; Ultupharma AB: Current equity holder in private company. Gustavsson:Vinnova: Honoraria; XSpray AB: Divested equity in a private or publicly-traded company in the past 24 months; Celgene: Divested equity in a private or publicly-traded company in the past 24 months; Bristol-Myers Squibb: Divested equity in a private or publicly-traded company in the past 24 months; Sangus Jazz AB: Current equity holder in private company; PiezoMotor AB: Current equity holder in publicly-traded company; Episurf AB: Current equity holder in publicly-traded company; Nanexa AB: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides AB: Current Employment, Current equity holder in publicly-traded company. Thuresson:Oncopeptides: Consultancy, Current equity holder in publicly-traded company; Statisticon: Current Employment. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. OffLabel Disclosure: This is a phase 2 investigational study of melflufe in RRMM.

Background: Brain tumours are the most common childhood tumours. Half of them are in the posterior fossa, where surgical removal is complicated by postoperative speech impairment (POSI) in up to 25% of patients. POSI manifests within days of surgery, while improvement takes weeks or months. The surgical approach to midline tumours, mostly undertaken by transvermian or telovelar routes, has been proposed to influence the risk of POSI. We investigated the risk of developing POSI, the time course of its resolution and its association with surgical approach and other clinical factors. Methods: 426 children aged 0–17·9 years undergoing primary surgery for a posterior fossa tumour at 26 centres in nine European countries were prospectively included. Speech was classified as either mutism, reduced or habitual at two weeks, two months, and one year after surgery. Findings: POSI developed in 30% of patients: Mutism in 15% (56/378) a median 1 day after surgery (IQR, 0–2; max 10) and reduced speech in 15% (58/378). In multivariate analysis, POSI was associated with using a telovelar approach (odds ratio (OR), 1·7; 95% CI, 1·03–2·9, p

Our purpose was to determine the role of CHRNA4 and CHRNB2 in insular epilepsy.We identified two patients with drug-resistant predominantly sleep-related hypermotor seizures, one harboring a heterozygous missense variant (c.77CT; p. Thr26Met) in the CHRNB2 gene and the other a heterozygous missense variant (c.1079GA; p. Arg360Gln) in the CHRNA4 gene. The patients underwent electrophysiological and neuroimaging studies, and we performed functional characterization of the p. Thr26Met (c.77CT) in the CHRNB2 gene.We localized the epileptic foci to the left insula in the first case (now seizure-free following epilepsy surgery) and to both insulae in the second case. Based on tools predicting the possible impact of amino acid substitutions on the structure and function of proteins (sorting intolerant from tolerant and PolyPhen-2), variants identified in this report could be deleterious. Functional expression in human cell lines of α4β2 (wild-type), α4β2-Thr26Met (homozygote), and α4β2/β2-Thr26Met (heterozygote) nicotinic acetylcholine receptors revealed that the mutant subunit led to significantly higher whole-cell nicotinic currents. This feature was observed in both homo- and heterozygous conditions and was not accompanied by major alterations of the current reversal potential or the shape of the concentration-response relation.This study suggests that variants in CHRNB2 and CHRNA4, initially linked to autosomal dominant nocturnal frontal lobe epilepsy, are also found in patients with predominantly sleep-related insular epilepsy. Although the reported variants should be considered of unknown clinical significance for the moment, identification of additional similar cases and further functional studies could eventually strengthen this association.

Background - 5-fluorouracil (5-FU) in combination with the folate leucovorin (LV) has formed the backbone of chemotherapy for advanced colorectal cancer for several decades. A number of genes encode proteins that participate in transportation of LV into the cells, as well as in subsequent metabolic action. We previously reported that high tumoral expression of genes involved in folate transport, polyglutamation, and metabolism was associated with decreased risk of recurrent disease in patients with stage III colorectal cancer treated with 5-FU + LV (FLV) alone, or in combination with oxaliplatin (FLOX) according to the Nordic bolus regimen. The aim of the present study was to determine the association between expression of the folate-associated genes ABCC3, MTHFD2, SLC19A1, SLC25A32, SLC46A1, and TYMS and outcome of patients with metastatic colorectal cancer subjected to palliative chemotherapy. Patients and Methods - A total of 290 patients treated with FLV (n = 113), FLOX (n = 102) or FLV + irinotecan (FLIRI, n = 75) were included. Relative gene expression (ΔCt) was determined in primary tumors by quantitative PCR and analyzed in relation to clinical benefit, based on RECIST criteria and 3-year progression-free survival (PFS). Analyses were conducted on the whole study group, and on subgroups based on tumor stage at primary surgery (subgroup 1, stage I-III; subgroup 2, stage IV). An ANOVA test was used to assess the relationship between expression and clinical benefit. A multivariate Cox proportional hazard model was applied to assess potential associations between genetic markers, clinical variables and PFS. A Stepwise model selection was used to identify a minimal set of variables associated with PFS. Results - Low expression of TYMS and MTHFD2, and high expression of ABCC3 was significantly associated with a clinical benefit in the whole group (p Conclusion - Expression of TYMS, the target enzyme of 5-FU, was strongly associated with clinical benefit in the whole group, whereas expression of TYMS and the folate transporters SLC25A32, and ABCC3 was associated with PFS in the subgroups (stage I-III and stage IV), respectively. The prospective global phase III study AGENT is presently conducted on patients with advanced colorectal cancer, to determine whether expression of these genes can predict response to 5-FU-based chemotherapy that includes LV or the novel folate arfolitixorin. Citation Format: Yvonne Wettergren, Elisabeth Odin, Göran Carlsson, Pushpa Saksena, Anders Edsjö, Alessandro Di Cara, Roger Tell, Bengt Gustavsson. Tumoral expression of folate-associated genes is associated with progression-free survival of patients with advanced colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 346.

Idiopathic intracranial hypertension (IIH) is a disorder affecting both the pediatric and adult population. Investigations and treatments may differ considerably. There are no evidence-based guidelines for treatment. During a national multidisciplinary meeting in Stockholm January 2018 IIH experts from several Swedish regions met to discuss how to manage this patient group. These guidelines are based on this meeting and a review of current medical knowledge. To summarize: All patients should be investigated and treated for underlying factors that could be the cause of high intracranial pressure (ICP) (such as obesity, secondary causes such as intracranial tumors or other factors reported to affect ICP). When treating IIH the preservation of vision is crucial. Follow-up depends on visual status. In case of acute risk of visual impairment prompt surgical intervention must be considered. Symptomatic treatment of headache is recommended.

OBJECTIVE Isolated nonsyndromic sagittal synostosis (SS) is the most common form of craniosynostosis in children, accounting for approximately 60% of all craniosynostoses. The typical cranial measurement used to define and follow SS is the cephalic index (CI). Several surgical techniques have been suggested, but agreement on type and timing of surgery is lacking. This study aimed to evaluate the authors’ institutional experience of surgically treating SS using a modified subtotal cranial vault remodeling technique in a population-based cohort. Special attention was directed toward the effect of patient age at time of surgery on long-term CI outcome. METHODS A retrospective analysis was conducted on all patients with isolated nonsyndromic SS who were surgically treated from 2003 to 2011. Data from electronic medical records were gathered. Eighty-two patients with SS were identified, 77 fulfilled inclusion criteria, and 72 had sufficient follow-up data and were included. CI during follow-up after surgery was investigated with ANOVA and a linear mixed model. RESULTS In total, 72 patients were analyzed, consisting of 16 females (22%) and 56 males (78%). The mean ± SD age at surgery was 4.1 ± 3.1 months. Blood transfusions were received by 81% of patients (26% intraoperatively, 64% postoperatively, 9% both). The mean ± SD time in the pediatric ICU was 1.1 ± 0.25 days, and the mean ± SD total hospital length of stay was 4.6 ± 2.0 days. No patient required reoperation. The mean ± SD CI increased from 69 ± 3 to 87 ± 5 for patients who underwent surgery before 45 days of age. Surgery resulted in a larger increase in CI for patients who underwent surgery at a younger age compared with older patients (p < 0.05, Tukey’s HSD test). In the comparison of patients who underwent surgery before 45 days of age with patients who underwent surgery at 45–90, 90–180, and more than 180 days of age, the linear mixed model estimated a long-term loss of CI of 3.0, 5.5, and 7.4 points, respectively. CONCLUSIONS The modified subtotal cranial vault remodeling technique used in this study significantly improved CI in patients with SS. The best results were achieved when surgery was performed early in life.

The objectives of this single-center, open-label, phase II study were to evaluate (a) the feasibility and safety of neoadjuvant administration of pemetrexed with oral folic acid and vitamin B12 (FA/B12) in newly diagnosed patients with resectable rectal cancer and (b) intracellular and systemic vitamin metabolism. Patients were treated with three cycles of pemetrexed (500 mg/m2, every 3 weeks) and FA/B12 before surgery. The reduced folates tetrahydrofolate, 5-methyltetrahydrofolate, and 5,10-methylenetetrahydrofolate were evaluated from biopsies in tumor tissue and in adjacent mucosa. Serum levels of homocysteine, cystathionine, and methylmalonic acid were also measured. All 37 patients received three cycles of pemetrexed; 89.2% completed their planned dosage within a 9-week feasibility time frame. Neither dose reductions nor study drug-related serious adverse events were reported. Reduced folate levels were significantly higher in tumor tissue compared with adjacent mucosa at baseline. After FA/B12 administration, tissue levels of reduced folates increased significantly and remained high during treatment in both tumor and mucosa until surgery. Serum levels of cystathionine increased significantly compared with baseline after FA/B12 administration, but then decreased, fluctuating cyclically during pemetrexed therapy. Homocysteine and methylmalonic acid levels decreased significantly after FA/B12 administration, and remained below baseline levels during the study. These results indicate that administration of three neoadjuvant cycles of single-agent pemetrexed, every 3 weeks, with FA/B12 in patients with resectable rectal cancer is feasible and tolerable. Tissue and serum vitamin metabolism results demonstrate the influence of pemetrexed and FA/B12 on vitamin metabolism and warrant further study.

T cell–mediated immunity is a major component of antitumor immunity. In order to be efficient, effector T cells must leave the circulation and enter into the tumor tissue. Regulatory T cells (Treg) from gastric cancer patients, but not from healthy volunteers, potently inhibit migration of conventional T cells through activated endothelium. In this study, we compared T cells from colon cancer patients and healthy donors to determine the mechanisms used by Tregs from cancer patients to inhibit conventional T-cell migration. Our results showed that circulating Tregs from cancer patients expressed high levels of CD39, an ectoenzyme mediating hydrolysis of ATP to AMP, as a rate-determining first step in the generation of immunosuppressive adenosine. Tumor-associated Tregs expressed even more CD39, and we therefore examined the importance of adenosine in Treg-mediated inhibition of T-cell transendothelial migration in vitro. Exogenous adenosine significantly reduced migration of conventional T cells from healthy volunteers, and blocking either adenosine receptors or CD39 enzymatic activity during transmigration restored the ability of conventional T cells from cancer patients to migrate. Adenosine did not directly affect T cells or endothelial cells, but reduced the ability of monocytes to activate the endothelium. Taken together, our results indicate that Treg-derived adenosine acts on monocytes and contributes to reduced transendothelial migration of effector T cells into tumors. This effect of Tregs is specific for cancer patients, and our results indicate that Tregs may affect not only T-cell effector functions but also their migration into tumors. Cancer Immunol Res; 4(3); 183–93. ©2016 AACR.

185 Background: 5-Fluorouracil (5FU) is one of the most commonly used cancer drugs. FdUMP is a metabolite from 5FU which inhibits thymidylate synthase (TS). TS inhibition causes a rise in the intracellular pool of the natural TS substrate dUMP leading to increased global levels of deoxyuridine (dUR). In order to increase TS inhibition, 5FU is combined with folates, usually leucovorin (LV). However, LV needs enzymatic conversion to become active. The LV conversion capacity differs between patients, with the consequence that many patients will have a reduced effect of 5FU-based treatment. Arfolitixorin is a biologically active folate, 5,10-methylenetetrahydrofolate, which doesn´t need enzymatic conversion; hence it could potentially be more efficacious. Methods: ISO-CC-005 is a phase I/II safety and tolerability study in mCRC patients receiving 5FU/arfolitixorin alone or in combination with irinotecan or oxaliplatin ± bevacizumab. Efficacy was evaluated as Overall Response Rate (ORR) after 4 cycles of chemotherapy. A LC-MS/MS method was developed for quantification of plasma dUr and 5FU. Blood samples were collected before and 24 h after 5FU administration at the first (C1) and fourth (C4) treatment cycle (n = 33). The C4/C1 ratio for dUr and 5FU, respectively, were calculated.The clinical response, which is an ordered categorical data, was modelled using nominal logistic regression using the ratio C4/C1 and the absolute values C1 and C4 as explanatory variables. Results: A positive correlation between dUr and 5FU levels was seen (r = 0.89, p = 0.0011) at C4. The C4/C1 ratio for dUr and 5FU in plasma correlated positively (r = 0.95, p = 0.0001). A positive correlation was also found between arfolitixorin dose and plasma levels of dUr (r = 0.44, p = 0.016) at C1, but not at C4. In the model test, the C4/C1 dUr ratio, as well as the individual dUr levels at C1 and C4, had a highly significant effect on ORR (p = 0.0075). Conclusions: The results demonstrate that the arfolitixorin dose has an impact on plasma levels of dUr and also on clinical response. dUr could potentially be an early surrogate marker for TS inhibition in mCRC patients treated with 5FU/arfolitixorin. Clinical trial information: NCT02244632.

Tumor-infiltrating lymphocytes are crucial for anti-tumor immunity. We have previously shown that regulatory T cells (Treg) are able to reduce T-cell transendothelial migration in vitro and accumulation of effector T cells in intestinal tumors in vivo. Treg depletion also resulted in increased levels of the chemokines CXCL9 and CXCL10 specifically in the tumors. In this study, we investigated the mechanisms for Treg mediated suppression of T-cell migration into intestinal tumors in the APCmin/+ mouse model. By breeding APCmin/+ mice with DEREG mice, which harbour a high affinity diphtheria toxin receptor under the control of the FOXP3 promoter, we were able to deplete Treg in tumor-bearing mice. Using adoptive transfer experiments, we could document a markedly increased migration of T cells specifically into Treg depleted tumors, and that Treg depletion results in increased production of the CXCR3 ligand CXCL10 from endothelial cells in the tumors. Furthermore, we were able to demonstrate that T cells use CXCR3 to migrate into intestinal tumors. In addition, human colon adenocarcinomas express high levels of mRNA CXCR3 ligands and tumor endothelial cells produce CXCL9 and CXCL10 ex vivo. In conclusion, this study demonstrates that Treg reduce endothelial CXCL10 production, inhibit T-cell migration into tumors and that CXCR3 mediated signalling is crucial for lymphocyte accumulation in intestinal tumors. Thus, immunotherapy aimed at Treg depletion may be effective by increasing not only T effector cell activity, but also their accumulation in tumors. Electronic supplementary material The online version of this article (10.1007/s00262-018-2161-9) contains supplementary material, which is available to authorized users.

Mucosa-associated invariant T (MAIT) cells are innate-like T cells with a conserved TCR α-chain recognizing bacterial metabolites presented on the invariant MHC-related 1 molecule. MAIT cells are present in intestinal tissues and liver, and they rapidly secrete IFN-γ and IL-17 in response to bacterial insult. In colon cancer, IL-17–driven inflammation promotes tumor progression, whereas IFN-γ production is essential for antitumor immunity. Thus, tumor-associated MAIT cells may affect antitumor immune responses by their secreted cytokines. However, the knowledge of MAIT cell presence and function in tumors is virtually absent. In this study, we determined the frequency, phenotype, and functional capacity of MAIT cells in colon adenocarcinomas and unaffected colon lamina propria. Flow cytometric analyses showed significant accumulation of MAIT cells in tumor tissue, irrespective of tumor stage or localization. Colonic MAIT cells displayed an activated memory phenotype and expression of chemokine receptors CCR6 and CCR9. Most MAIT cells in unaffected colon tissues produced IFN-γ, whereas only few produced IL-17. Colonic MAIT cells also produced TNF-α, IL-2, and granzyme B. In the tumors, significantly lower frequencies of IFN-γ–producing MAIT cells were seen, whereas there were no differences in the other cytokines analyzed, and in vitro studies showed that secreted factors from tumor tissue reduced IFN-γ production from MAIT cells. In conclusion, MAIT cells infiltrate colon tumors but their ability to produce IFN-γ is substantially reduced. We suggest that MAIT cells have the capacity to promote local immune responses to tumors, but factors in the tumor microenvironment act to reduce MAIT cell IFN-γ production.

Angiolipomas are benign tumors usually manifested as subcutaneous nodules. Rarely they may form spinal extradural masses. These spinal cavernous angiolipomas have mostly been described in adults. To our knowledge, spinal cavernous angiolipomas have been reported in nine pediatric patients. In this paper, we present a 1-year-old child presenting with a spontaneous spinal epidural hematoma from a spinal cavernous angiolipoma and highlight the importance of conducting a histopathological analysis of spontaneous hematomas in previously healthy children.

Herein we present a historical review of the development of systemic chemotherapy for colorectal cancer (CRC) in the metastatic and adjuvant treatment settings. We describe the discovery of 5-fluorouracil (5-FU) by Heidelberger and colleagues in 1957, the potentiation of 5-FU cytotoxicity by the reduced folate leucovorin, and the advent of novel cytotoxic agents, including the topoisomerase I inhibitor irinotecan, the platinum-containing agent oxaliplatin, and the 5-FU prodrug capecitabine. The combination therapies, FOLFOX (5-FU/leucovorin and oxaliplatin) and FOLFIRI (5-FU/leucovorin and irinotecan), have become established as efficacious cytotoxic regimens for the treatment of metastatic CRC, resulting in overall survival times of approximately 2 years. When used as adjuvant therapy, FOLFOX also improves survival and is now the gold standard of care in this setting. Biological agents have been discovered that enhance the effect of cytotoxic therapy, including bevacizumab (a humanized monoclonal antibody that targets vascular endothelial growth factor, a central regulator of angiogenesis) and cetuximab/panitumumab (monoclonal antibodies directed against the epidermal growth factor receptor). Despite the ongoing development of novel antitumor agents and therapeutic principles as we enter the era of personalized cancer medicine, systemic chemotherapy involving infusional 5-FU/leucovorin continues to be the cornerstone of treatment for patients with CRC.

Background: Craniopharyngiomas are frequent hypothalamo-pituitary tumors in children, presenting predominantly as cystic lesions. Morbidity from conventional treatment has focused attention on intracystic drug delivery, hypothesized to cause fewer clinical consequences. However, the efficacy of intracystic therapy remains unclear. We report the retrospective experiences of several global centers using intracystic interferon-alpha.Methods: European Societe Internationale d'Oncologie Pediatrique and International Society for Pediatric Neurosurgery centers were contacted to submit a datasheet capturing pediatric patients with cystic craniopharyngiomas who had received intracystic interferon-alpha. Patient demographics, administration schedules, adverse events, and outcomes were obtained. Progression was clinical or radiological (cyst reaccumulation, novel cysts, or solid growth).Results: Fifty-six children (median age, 6.3 y) from 21 international centers were identified. Median follow-up from diagnosis was 5.1 years (0.3-17.7 y). Lesions were cystic (n = 22; 39%) or cystic/solid (n = 34; 61%). Previous progression was treated in 43 (77%) patients before interferon use. In such cases, further progression was delayed by intracystic interferon compared with the preceding therapy for cystic lesions (P = 0.0005). Few significant attributable side effects were reported. Progression post interferon occurred in 42 patients (median 14 mo; 0-8 y), while the estimated median time to definitive therapy post interferon was 5.8 (1.8-9.7) years.Conclusions: Intracystic interferon-alpha can delay disease progression and potentially offer a protracted time to definitive surgery or radiotherapy in pediatric cystic craniopharyngioma, yet demonstrates a favorable toxicity profile compared with other therapeutic modalities-important factors for this developing age group. A prospective, randomized international clinical trial assessment is warranted.

Central nervous system tumours constitute 25% of all childhood cancers; more than half are located in the posterior fossa and surgery is usually part of therapy. One of the most disabling late effects of posterior fossa tumour surgery is the cerebellar mutism syndrome (CMS) which has been reported in up to 39% of the patients but the exact incidence is uncertain since milder cases may be unrecognized. Recovery is usually incomplete. Reported risk factors are tumour type, midline location and brainstem involvement, but the exact aetiology, surgical and other risk factors, the clinical course and strategies for prevention and treatment are yet to be determined. This observational, prospective, multicentre study will include 500 children with posterior fossa tumours. It opened late 2014 with participation from 20 Nordic and Baltic centres. From 2016, five British centres and four Dutch centres will join with a total annual accrual of 130 patients. Three other major European centres are invited to join from 2016/17. Follow-up will run for 12 months after inclusion of the last patient. All patients are treated according to local practice. Clinical data are collected through standardized online registration at pre-determined time points pre- and postoperatively. Neurological status and speech functions are examined pre-operatively and postoperatively at 1–4 weeks, 2 and 12 months. Pre- and postoperative speech samples are recorded and analysed. Imaging will be reviewed centrally. Pathology is classified according to the 2007 WHO system. Germline DNA will be collected from all patients for associations between CMS characteristics and host genome variants including pathway profiles. Through prospective and detailed collection of information on 1) differences in incidence and clinical course of CMS for different patient and tumour characteristics, 2) standardized surgical data and their association with CMS, 3) diversities and results of other therapeutic interventions, and 4) the role of host genome variants, we aim to achieve a better understanding of risk factors for and the clinical course of CMS - with the ultimate goal of defining strategies for prevention and treatment of this severely disabling condition. Clinicaltrials.gov : NCT02300766 , date of registration: November 21, 2014.

5-fluorouracil (5-FU) competes with uracil (Ura) as a substrate for dihydropyrimidine dehydrogenase (DPD). Low DPD activity impairs breakdown of Ura to dihydrouracil (UH2) and is associated with toxicity during 5-FU-based chemotherapy. Calculation of the 5-FU dose is based on body surface area, and new tools are needed to individualize treatment. The aim of study was to measure Ura and UH2 in saliva of patients with colorectal cancer and relate levels to treatment-induced toxicity. Saliva was collected from 73 patients with stage III colorectal cancer prior to adjuvant 5-FU-based treatment. Ura and UH2 were analyzed by a column-switching HPLC method. Toxicity was evaluated before each treatment cycle and the highest grade was noted at end of treatment. Toxicity was more common and severe among women compared with men. The Ura and UH2 concentrations in saliva were 5.0 ± 6.8 and 5.0 ± 4.0 nmol/ml, respectively. The UH2/Ura ratio was lower in women compared with men (1.2 ± 1.0 and 2.2 ± 2.5, respectively, p = 0.0026). Patients who needed to reduce the drug dose during treatment (or terminate treatment) due to toxicity had a lower ratio (1.3 ± 0.85) compared to patients who completed treatment without dose reduction (4.1 ± 4.3, p

Purpose – This study aims to formulate recommendations for business-to-business (B2B) researchers, with the potential to increase the extent to which B2B research is relevant to managers. Design/methodology/approach – These recommendations are derived from and inspired by the grounded theory methodology. Findings – In this article, we argue that conceptualizations which are potentially relevant to managers are those that discover new perspectives, simplify complexity, enable managers to take action and have an instant grab. To accomplish this as researchers, the authors emphasize fostering a beginner’s mind, creating umbrella models, increasing the level of abstraction of concepts and finding the core process in data. Originality/value – In this article, we translate the basic principles within the grounded theory methodology into more general recommendations that can be used by B2B researchers.

Background No biomarkers predict efficacy of 5-FU for metastatic colorectal cancer (mCRC). A gene expression based drug response predictor (DRP) had been shown to predict benefit of 5-FU in the PETACC-3 cohort [1]. The current study aimed to validate the biomarker in a cohort of mCRC patients. Methods 100 mCRC patients treated with 5-FU and leucovorin (FLV) at Sahlgrenska University Hospital from 1996-2013 had mRNA isolated from pretreatment formalin-fixed paraffin embedded tumor tissue and run on Affymetrix HG-133_Plus_2 microarray. The DRP is based on correlations of in-vitro cytotoxicity to 5-FU and consequently correlations to mRNA expression of 3.500 tumors and evaluated blinded to outcome. Primary outcome was progression-free-survival (PFS) at 3 years after treatment with FLV. In addition to variables in the table, right vs left colon cancer vs rectal cancer, age, gender and surgery elective or acute were assessed in the multivariate model. Treatments in the metastatic setting included oxaliplatin and irinotecan from year 2000. To correct for possible selection bias for FLV-treatment, we corrected for treatment year 2000 in the analysis plan. Results The DRP was able to predict benefit of FLV in patients treated after 2000 (n = 73) with a univariate hazard ratio (HR) of 0.60 (95% confidence interval (CI) 0.38-0.93, p = 0.023) for a 50% difference of the DRP. For patients treated before 2000 results were not statistically significant. In the Cox model including all variables, a DRP score of 90 corresponds to a 50% likelihood of 9 months PFS and a score of 32 corresponds to a PFS of 6 months. Table . 644P Multivariate analysis of PFS Variable Level HR 95%-CI P-value DRP, difference of 50 Treatment before 2000 1.24 0.52-3.03 0.63 Treatment after 2000 0.47 0.28-0.78 0.004 Grade of differentiation Medium + high vs low 0.48 0.29-0.80 0.005 Mucinous vs low 0.32 0.13-0.83 0.019 Performance status 2 vs 0-1 2.65 1.41-4.97 0.002 Conclusions In patients treated with 5-FU after 2000 the DRP appears to predict benefit. There are no obvious reasons for the lack of prediction before 2000 but options include mRNA degradation, change in handling of samples, or the selection of older patients after 2000. [1] PLOS ONE; 11(5): e0155123. Legal entity responsible for the study Oncology Venture. Funding Oncology Venture. Disclosure I.K. Buhl: Full / Part-time employment, Shareholder (immediate family): Oncology Venture. B. Gustavsson: Shareholder / Stockholder / Stock options: Isofol. I.J. Christensen: Advisory / Consultancy, Shareholder / Stockholder / Stock options: Oncology Venture. A. Hansen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Oncology Venture. S. Knudsen: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Oncology Venture. P.B. Jensen: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Oncology Venture. All other authors have declared no conflicts of interest.

Experimental teratoma induced from human pluripotent stem cells with normal karyotype can be described as a failed embryonic process and includes besides advanced organoid development also large elements of tissue with a prolonged occurrence of immature neural components. Such immature components, although benign, exhibit strong morphological resemblance with tumors of embryonic neuroectodermal origin. Here, we demonstrate that biopsy material from childhood tumors of neural embryonic origin transplanted to mature experimental teratoma can show an exclusive preference for matching tissue. Tumor specimens from five children with; Supratentorial primitive neuroectodermal tumor (sPNET); Pilocytic astrocytoma of the brainstem; Classic medulloblastoma; peripheral primitive neuroectodermal tumor (pPNET) or neuroblastoma (NB), respectively, were transplanted. Analysis of up to 120 sections of each tumor revealed an engraftment for three of the transplanted tumors: pPNET, sPNET, and NB, with a protruding growth from the latter two that were selected for detailed examination. The histology revealed a strict tropism with a non-random integration into what morphologically appeared as matched embryonic microenvironment recuperating the patient tumor histology. The findings suggest specific advantages over xenotransplantation and lead us to propose that transplantation to the human embryonic microenvironment in experimental teratoma can be a well-needed complement for preclinical in vivo studies of childhood neuroectodermal tumors.

Recruitment of immune cells to tumors is a complex process crucial for both inflammation-driven tumor progression and specific anti-tumor cytotoxicity. Chemokines control the directed migration of immune cells, and their actions are partly controlled by nonsignaling chemokine decoy receptors. The role of the receptors such as D6, Duffy antigen receptor for chemokines and ChemoCentryx chemokine receptor in immunity to tumors is still unclear. Using real-time PCR, we detected significantly decreased expression of D6 mRNA in colon tumors compared to unaffected mucosa. D6 protein was expressed by lymphatic endothelium and mononuclear cells in the colon lamina propria and detected by immunohistochemistry in two out of six tissue samples containing high D6 mRNA levels, whereas no staining was observed in any tissue samples expressing low mRNA levels. When examining the density of lymphatic vessels in colon tumors, we detected a marked increase in vessels identified by the lymphatic endothelial marker Lyve-1, excluding passive regulation of D6 due to decreased lymphatic vessel density. In parallel, the Treg-recruiting chemokine CCL22, which is sequestered by D6, was threefold increased in tumor tissue. Furthermore, we could show that low D6 expression correlated to more invasive tumors and that tumor location influences D6 expression, which is lower in the more distal parts of the colon. The data support that regulation of D6 by colon tumors results in altered levels of proinflammatory CC chemokines, thereby shaping the local chemokine network to favor tumor survival. This may have implications for the design of future immunotherapy for colon cancer.

Local inflammation is a strong risk factor for the development of gastrointestinal adenocarcinomas. Mucosal regulatory T cells and IgA-secreting cells both contribute to reduce inflammatory responses, and their recruitment to tissues is dependent on local production of chemokines. More specifically, IgA-secreting cells are recruited to mucosal tissues by CCL28 signalling through CCR10. Here, we examined the recruitment of IgA-secreting plasma cells to tumor-associated mucosa in patients suffering from colon adenocarcinoma. Flow cytometric analyses of single cell suspensions from tumor-associated and unaffected colon mucosa showed a marked decrease in CD19(+)CD38(high)IgA(+) plasmablasts in the tumor-associated mucosa, while the total frequencies of B and T cells were similar. This finding was confirmed in ELISPOT assays, demonstrating a 64 % reduction in the frequencies of IgA-secreting cells among cells from the tumor-associated mucosa. The few IgA(+) plasmablasts present in the tumor did not express CCR10, and functional migration assays demonstrated that IgA-secreting cells from tumor-associated mucosa did not migrate in response to CCL28. Taken together, our results show an impaired migration of IgA-secreting cells to colon tumors, presumably caused by a decreased production of CCL28 in the tumor. The lack of local IgA antibodies may lead to impaired barrier function and increased bacterial colonization, driving further inflammatory responses and promoting tumor growth.

Purpose The purpose of this study is to conceptualize and analyse novice researchers experiences of the Glaserian grounded theory methodology. Design/methodology/approach The gorunded theory analytical procedures were applied. Findings The paper suggests that the creative freedom inherited in the Glaserian grounded theory approach empowers novice researchers, and many students reported positive emotions related to this freedom. At the same time, this freedom can represent a difficulty. Several students thought the tabula rasa instruction was something of a paradox, and the instructions within the methodology to “be without preconceptions”, “let the theory emerge”, and “find the social process” was difficult for most students to understand. However, some students found that they could counteract this difficulty via a systematic coding process and by working in pairs that enabled them to conduct an analytical dialogue. Originality/value This is the first study that investigates the way that novice researchers experience the Glaserian grounded theory methodology.

A liquid chromatography electrospray ionization tandem mass spectrometry (LC-MS/MS) method has been developed for the determination of 5,10-methylenetetrahydrofolate (methyleneTHF), tetrahydrofolate (THF) and 5-methyltetrahydrofolate (methylTHF) in colorectal mucosa and tumor tissues. The folate extraction method includes homogenization, heat and folate conjugase treatment to hydrolyze polyglutamyl folate to monoglutamyl folate. Before analysis on LC-MS/MS, simple and fast sample purification with ultrafiltration (molecular weight cut-off membrane, 10 kDa) was performed. Folates were detected and quantified using positive electrospray. The method described in the present paper was successfully applied to determine the level of three folate monoglutamates in mucosa and tumor samples from 77 colorectal cancer patients, starting from a limited amount of tissue. The results showed that the LC-MS/MS method has a great advantage over other previously used methods because of its high sensitivity and selectivity. Significantly higher levels of methyleneTHF and THF were found in tumor compared with matched mucosa tissues. Folate levels in adjacent mucosa were associated with tumor location, age and gender. The correlation between folate levels and tumor site further strengthens the fact that development of right- and left-sided tumors follows different pathways. Copyright © 2012 John Wiley & Sons, Ltd.

Aim Local recurrence is an important endpoint of rectal cancer treatment, but details of this form of treatment failure are less well described. The aim of this study was to acquire deeper knowledge of local recurrence regarding symptoms, diagnostic work-up, clinical management, health-care utilization and outcome. Method Of 671 patients with rectal cancer, 57 were diagnosed with local recurrence within 5 years after surgery. Their records were analysed. Results At diagnosis of local recurrence 49 (86%) of 57 patients were symptomatic and 40 (70%) were diagnosed between scheduled follow-up visits. The predominant symptom was pain. Forty-five of the 57 (79%) had a palpable tumour. Most were deemed incurable at presentation and 10 (18%) were operated on with curative intent. Five years after the initial rectal cancer surgery, two patients were alive, with one free of disease. Despite the need for multiple interventions, including surgery, only four out of 40 patients were classified as being well-palliated in the terminal stage. Conclusion Follow-up after rectal cancer surgery by annual clinical examination is not sufficient to detect local recurrence when it is asymptomatic. Local recurrence of rectal cancer is often associated with intractable symptoms. These patients require frequent interventions and can rarely be cured if diagnosed at an advanced stage. Strategies for early detection of local recurrence and the management thereof require improvement.

Approximately 20-25% of patients with colorectal cancer present with liver metastases at the time of diagnosis. Traditionally, resection of the primary tumor has been advocated in order to prevent complications of the primary tumor colorectal cancer in patients with synchronous liver metastases. The published data concerning long-term prognosis in this group of patients are discordant. Although some of the reports show survival benefits from resection of the primary tumor, these studies are retrospective with small number of patients and using single drug chemotherapy. For patients with resectable liver metastases, new studies indicate that progression-free survival is best in patients receiving perioperative chemotherapy. In patients with synchronous nonresectable liver metastases and colorectal cancer, there is no published prospective randomized study comparing initial surgery of the primary tumor with neoadjuvant chemotherapy. However, recent publications show that in patients receiving chemotherapy based on oxaliplatin or irinotecan combined with targeted treatments, the complications associated with the primary tumor are less than 10%. The conclusion should be that today prophylactic surgery of asymptomatic primary colorectal cancer in patients with liver metastases cannot be recommended.

The aim was to assess the feasibility of preoperative chemotherapy and possible tumour response using Pemetrexed (Alimta) in rectal cancer.The study was a prospective, non-randomized, single-centre phase I/II feasibility trial. 37 patients with resectable rectal cancer were recruited and given three 3-week cycles of preoperative Pemetrexed therapy. Tumour size and stage were assessed by MRI scans before and after chemotherapy. Treatment tolerability and response such as changes in tumour size and symptoms were assessed.All patients completed the chemotherapy. Whilst mild side effects were frequent (grade 1, 34/37), the risk of severe effects was limited (grade 3 or 4, 4/37). Overall, there was a significant reduction in tumour size (p0.001). By RECIST criteria, one patient had tumour progression, 23/36 had stable disease and 12 patients had a response of up to 65%. There was also a significant decrease in the number of pre-treatment symptoms (p0.018) including reduction of bleeding and diarrhoea/constipation.Preoperative (Neoadjuvant) treatment with Pemetrexed was feasible in studied patients. Serious side effects were limited and a radiological tumour response or stable disease was seen in a majority of patients.

Object Early-onset, nonidiopathic spine deformities are frequently caused by intraspinal anomalies necessitating both neurosurgical and orthopedic intervention. The clinical tradition at most treatment units is to perform neurosurgical and orthopedic procedures separately. Sometimes the deformity correction surgery is also done in stages, which leads to several periods of hospitalization, increased use of health care resources, and a long rehabilitation time for the patient. The purpose of this project was to perform an outcome survey for major spine surgery in high-risk patients, and to analyze whether an additional neurosurgical intervention during the same session increased the risk of complications. Methods A consecutive series of 81 patients with major rigid spine deformities treated by the same orthopedic surgeon was analyzed. In 24 of 81 cases there were additional intraspinal pathological entities indicating a neurosurgical procedure. All cases were divided into 2 groups: one with anterior-posterior surgery and also neurosurgery, and the other with anterior-posterior surgery but without neurosurgery. The result variables for the group comparisons were as follows: clinical and radiographic outcome, operating time, length of intensive care and hospital stay, relative blood loss, and occurrence of complications or adverse events. Groups were similar in terms of sex, size of spinal curve, and surgical procedures, but different in terms of diagnosis (there were more patients with myelomeningocele in the group treated with both anterior-posterior surgery and neurosurgery) and patient age (the group with both anterior-posterior surgery and neurosurgery was younger). Results An additional neurosurgical procedure combined with fusion surgery did not increase the complication rate or use of resources compared with fusion surgery alone, except in the length of operating time. The mean correction of the spinal curve was 56.7%, and the mean correction of the pelvic obliquity was 74.7%. The loss of correction was 3° on average. A more than 10° progression was seen in 9 cases. There were no deaths, and there were no neurological complications or surgery-related deterioration of ambulatory function. There were 10 complications that altered the planned postoperative course, including 5 infections. Conclusions One-stage major spine surgery, even when neurosurgery is included, is safe and does not increase the risk of complications. The increase in hospital and ICU stays is marginal.