Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative.

BACKGROUND: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. MATERIAL AND METHODS: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. RESULTS: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. CONCLUSION: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting.

Update on the treatment of advanced cervical cancer.

In this review we discuss the most important issues concerning the treatment of advanced cervical cancer. Advances in the treatment of cervical cancer are made slowly, but recently the data from five important randomised studies gave rise to an important change in the standard treatment of this disease. For the new standard in advanced cervical cancer, it is clear that chemotherapy should be added to the radiation regimen for an optimal treatment. However, firm conclusions to which drugs or regimens cannot be drawn at this moment.

Treatment of metastatic invasive moles in two husband-side sisters-in-law. Case reports and review of literature.

PURPOSE OF INVESTIGATION: The treatment of "high risk" persistent trophoblastic disease (PTD) consists of poly-chemotherapy. This policy probably will lead to overtreatment of some patients. Also, familiar molar pregnancies through the paternal line are unknown in the literature up till now. METHODS: We describe two cases of "high risk" PTD in two husband-side sisters-in-law, in which poly-chemotherapy was stopped after histology became available and showed invasive metastatic mole. CONCLUSION: It should be stressed that treatment decisions should be made based on the concept of "high" or "low" risk PTD, but if histology becomes available, chemotherapy might be less aggressive in cases of invasive mole. If invasive mole could be familiar through the paternal line remains unclear with the current knowledge of genetics in trophoblastic disease.

In vitro upregulation of carcinoembryonic antigen expression by combinations of cytokines.

Interferons are able to enhance the expression of carcinoembryonic antigen (CEA) on tumour cells, allowing improved tumour targeting. In this report the hypothesis is tested that combinations of cytokines may further increase the tumour antigen expression. The combination of both IFN-gamma and IFN-alpha with interleukin-6 demonstrated a significant additive effect on the CEA-expression. This was found by quantitatively analysing the CEA-expression on human colorectal tumour cells by flow cytometry. It is concluded that combinations of cytokines show the potential of inducing tumour antigen expression for improved tumour targeting.

Clinical evidence of efficient tumor targeting based on single-chain Fv antibody selected from a combinatorial library.

We present a system for cancer targeting based on single-chain Fv (scFv) antibodies selected from combinatorial libraries, produced in bacteria and purified by using an engineered tag. Combinatorial libraries of scFv genes contain great diversity, and scFv antibodies with characteristics optimized for a particular task can be selected from them using filamentous bacteriophage. We illustrate the benefits of this system by imaging patients with carcinoembryonic antigen (CEA)-producing cancers using an iodine-123 labeled scFv anti-CEA selected for high affinity. All known tumor deposits were located, and advantages over current imaging technology are illustrated. ScFvs are produced in a cloned form and can be readily engineered to have localizing and therapeutic functions that will be applicable in cancer and other diseases.

Technetium-99m radiolabeling using a phage-derived single-chain Fv with a C-terminal cysteine.

UNLABELLED: Single-chain Fv (scFv) antibody fragments have potential for clinical imaging because of their rapid tumor penetration and high tumor-to-tissue ratios at early time points. ScFvs clear rapidly from the circulation so radiolabels such as 99mTc which have short half-lives are desirable, but the free thiol groups necessary for labeling with 99mTc are not normally found on these molecules. METHODS: We constructed a vector which enabled a free cysteine to be linked to the C-terminus of scFvs. MFE-23, a scFv directed against carcinoembryonic antigen (CEA), was cloned into this vector and cys-tagged MFE-23 was labeled with 99mTc using a D-glucarate transfer method. RESULTS: The radiolabeled product was stable in vivo and in vitro and showed favorable tumor-to-blood ratios in vivo at early time points (4:1 at 24 hr and 8:1 at 48 hr), although high kidney levels were also detected. CONCLUSION: Our study demonstrates an effective method to enable scFvs radiolabeling with 99mTc and also shows the potential of using a 99mTc-labeled scFv for clinical imaging studies.

A single chain Fv derived from a filamentous phage library has distinct tumor targeting advantages over one derived from a hybridoma.

Single-chain antibodies (scFvs) can be derived from a monoclonal antibody (MAb) or produced directly using filamentous phage technology, where antibodies with desired binding and purification characteristics can be readily selected from libraries. To test the hypothesis that the latter approach is more useful, we compared 2 anti-carcinoembryonic antigen (CEA) scFvs produced by these 2 different approaches. Our study showed that, both in the purification process and in the biodistribution pattern, MFE-23, produced by filamentous phage technology, gave favourable results compared to A5-SC, which is derived from the A5B7 MAb. This indicates the value of the filamentous phage approach for obtaining tumour-targeting scFvs.