FLOT Versus FLOT/Trastuzumab/Pertuzumab Perioperative Therapy of Human Epidermal Growth Factor Receptor 2-Positive Resectable Esophagogastric Adenocarcinoma: A Randomized Phase II Trial of the AIO EGA Study Group.

Purpose: High pathologic complete response (pCR) rates and comparably good survival data were seen in a phase II trial combining perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy with trastuzumab for resectable, esophagogastric adenocarcinoma (EGA). The current trial evaluates the addition of trastuzumab and pertuzumab to FLOT as perioperative treatment for human epidermal growth factor receptor 2-positive resectable EGA.

Methods: In this multicenter, randomized phase II/III trial, patients with human epidermal growth factor receptor 2-positive, resectable EGA (≥ clinical tumor 2 or clinical nodal-positive) were assigned to four pre- and postoperative cycles of either FLOT alone (arm A) or combined with trastuzumab and pertuzumab, followed by nine cycles of trastuzumab/pertuzumab (arm B).

Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial.

Background: Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma. This study reports on the safety and efficacy of the docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) as a perioperative therapy for patients with locally advanced, resectable tumours.

Methods: In this controlled, open-label, phase 2/3 trial, we randomly assigned 716 patients with histologically-confirmed advanced clinical stage cT2 or higher or nodal positive stage (cN+), or both, resectable tumours, with no evidence of distant metastases, via central interactive web-based-response system, to receive either three pre-operative and three postoperative 3-week cycles of 50 mg/m epirubicin and 60 mg/m cisplatin on day 1 plus either 200 mg/m fluorouracil as continuous intravenous infusion or 1250 mg/m capecitabine orally on days 1 to 21 (ECF/ECX; control group) or four preoperative and four postoperative 2-week cycles of 50 mg/m docetaxel, 85 mg/m oxaliplatin, 200 mg/m leucovorin and 2600 mg/m fluorouracil as 24-h infusion on day 1 (FLOT; experimental group).

Dual-targeting triplebody 33-16-123 (SPM-2) mediates effective redirected lysis of primary blasts from patients with a broad range of AML subtypes in combination with natural killer cells.

A number of agents designed for immunotherapy of Acute Myeloid Leukemia (AML) are in preclinical and early clinical development. Most of them target a single antigen on the surface of AML cells. Here we describe the development and key biological properties of a tri-specific agent, the dual-targeting triplebody SPM-2, with binding sites for target antigens CD33 and CD123, and for CD16 to engage NK cells as cytolytic effectors.

MicroRNA-192-5p is a predictive biomarker of survival for Stage IIIB colon cancer patients.

Background: The poor clinical prognosis of Stage IIIB colon cancer patients is due in part to the current lack of an effective diagnostic method being available and highlights a need for the identification of novel biomarkers like microRNA (miRNA).

Patients And Methods: We used microarray analysis to compare the miRNA expression profiles of eight Stage IIIB colon cancer patients with worse clinical outcome (those who developed liver metastases between 8 and 18 months after surgery) against eight 'cured' Stage IIIB colon cancer patients (those who remained disease free following surgery during the same monitoring period). In addition, quantitative real-time polymerase chain reaction (qRT-PCR) analysis was performed examining miRNAs in tumor tissue of 98 patients with Stage IIIB colon cancer.

Evidence for an Association of ERCC1 Expression and Mismatch Repair Status with Overall Survival in Colorectal Cancer Patients.

Background: The aim in this study was to determine if an association of excision repair cross-complementing group 1 (ERCC1) gene and mismatch repair (MMR) status with overall survival (OS) could be found from our analysis of a large cohort of Chinese colorectal cancer patients (CRC).

Methods: In total, 2,233 tissue samples isolated from individual CRC tumors were assessed by immunohistochemistry for the expression of ERCC1 and 4 MMR genes.

Results: The rates of proficient MMR (pMMR) and ERCC1 expression were 89.

Systematic immunohistochemical screening for mismatch repair and ERCC1 gene expression from colorectal cancers in China: Clinicopathological characteristics and effects on survival.

Background: We performed a systematic screening of colorectal cancer (CRC) tissues to investigate whether mismatch repair (MMR) status and ERCC1 protein expression could be predictive of clinical outcomes for these patients following the recommendation of The Evaluation of Genomic Applications in Practice of Prevention (EGAPP).

Methods: The expression of four MMR genes and ERCC1 were assessed by immunohistochemistry (IHC) from cancer tissue samples of 2233 consecutive CRC patients.

Results: We observed that most CRC patients with a proficient MMR (pMMR) status tended to have simultaneous ERCC1 protein expression (P< 0.

Impact of age and mismatch repair status on survival in colorectal cancer.

Previous studies have suggested that deficiencies in mismatch repair genes (dMMR) often occur in patients with colorectal cancer (CRC) and contribute to disease etiology. Here, we looked for a correlation of MMR status to disease outcomes from a large number of Chinese CRC patients stratified by the age of onset of disease. A total of 2233 CRC patients were analyzed and tissue biopsies of surgically removed tumors scored for MMR gene status.

A relationship to survival is seen by combining the factors of mismatch repair status, tumor location and age of onset in colorectal cancer patients.

Background: The progression of colorectal cancer (CRC) may differ depending on the location of the tumor and the age of onset of the disease. Previous studies also suggested that the molecular basis of CRC varies with tumor location, which could affect the clinical management of patients. Therefore, we performed survival analysis looking at different age groups and mismatch repair status (MMR) of CRC patients according to primary tumor location in an attempt to identify subgroups of CRC that might help in the prognosis of disease.

Association between Ki67 Index and Clinicopathological Features in Colorectal Cancer.

Background: Conflicting results have been reported about the association between the Ki67 labeling index (Ki67-Li) and clinical outcome in patients with colorectal cancer (CRC).

Patients And Methods: Ki67 expression was assessed by immunohistochemistry (IHC) in 2,233 consecutive CRC cases.

Results: We determined 992 cases to have a low and 1,241 cases to have a high Ki67-Li (representing an approximately 44-56% breakdown in distribution between low versus high patients designated by phenotype).

CD19-specific triplebody SPM-1 engages NK and γδ T cells for rapid and efficient lysis of malignant B-lymphoid cells.

Triplebodies are antibody-derived recombinant proteins carrying 3 antigen-binding domains in a single polypeptide chain. Triplebody SPM-1 was designed for lysis of CD19-bearing malignant B-lymphoid cells through the engagement of CD16-expressing cytolytic effectors, including NK and γδ T cells.SPM-1 is an optimized version of triplebody ds(19-16-19) and includes humanization, disulfide stabilization and the removal of potentially immunogenic sequences.

Dual-targeting triplebody 33-3-19 mediates selective lysis of biphenotypic CD19+ CD33+ leukemia cells.

Simultaneous targeting of multiple tumor-associated antigens (TAAs) in cancer immunotherapy is presumed to enhance tumor cell selectivity and to reduce immune escape.The combination of B lymphoid marker CD19 and myeloid marker CD33 is exclusively present on biphenotypic B/myeloid leukemia cells. Triplebody 33-3-19 binds specifically to both of these TAAs and activates T cells as immune effectors.

Chip-based platform for dynamic analysis of NK cell cytolysis mediated by a triplebody.

Cancer therapy via redirected lysis mediated by antibodies and antibody-derived agents relies on the availability of substantial numbers of sufficiently active immune effector cells. To monitor antitumor responses before and during therapy, sensitive methods are needed, capable of quantitating specific lysis of target cells. Here we present a chip-based single-cell cytometric assay, which uses adherent human target cells arrayed in structured micro-fields.

Hematologic Malignancies in Pregnancy: Management Guidelines From an International Consensus Meeting.

Purpose: The incidence of hematologic malignancies during pregnancy is 0.02%. However, this figure is increasing, as women delay conception until a later age.

The cost-effectiveness of UGT1A1 genotyping before colorectal cancer treatment with irinotecan from the perspective of the German statutory health insurance.

Background: The evidence concerning the cost-effectiveness of UGT1A1*28 genotyping is ambiguous and does not allow drawing valid conclusions for Germany. This study evaluates the cost-effectiveness of UGT1A1 genotyping in patients with metastatic colorectal cancer undergoing irinotecan-based chemotherapy compared to no testing from the perspective of the German statutory health insurance.

Material And Methods: A decision-analytic Markov model with a life time horizon was developed.

The ethics of deep brain stimulation (DBS).

Deep brain stimulation (DBS) is an invasive technique designed to stimulate certain deep brain regions for therapeutic purposes and is currently used mainly in patients with neurodegenerative disorders, such as Parkinson's disease. However, DBS is also used increasingly for other experimental applications, such as the treatment of psychiatric disorders (e.g.

T cell-recruiting triplebody 19-3-19 mediates serial lysis of malignant B-lymphoid cells by a single T cell.

Triplebody 19-3-19, an antibody-derived protein, carries three single chain fragment variable domains in tandem in a single polypeptide chain. 19-3-19 binds CD19-bearing lymphoid cells via its two distal domains and primary T cells via its CD3-targeting central domain in an antigen-specific manner. Here, malignant B-lymphoid cell lines and primary cells from patients with B cell malignancies were used as targets in cytotoxicity tests with pre-stimulated allogeneic T cells as effectors.

Root resorption caused by jaw infiltration of multiple myeloma: report of a case and literature review.

Introduction: Infiltration of the maxillofacial region by multiple myeloma is common and typically appears as punched out osteolytic lesions of the jaws. Although swelling, bone pain, and tooth mobility are characteristic clinical symptoms, root resorption is rare in conjunction with myeloma nests.

Methods: A case of a 67-year-old man with multiple myeloma is presented.

Phage idiotype vaccination: first phase I/II clinical trial in patients with multiple myeloma.

Background: Multiple myeloma is characterized by clonal expansion of B cells producing monoclonal immunoglobulins or fragments thereof, which can be detected in the serum and/or urine and are ideal target antigens for patient-specific immunotherapies.

Methods: Using phage particles as immunological carriers, we employed a novel chemically linked idiotype vaccine in a clinical phase I/II trial including 15 patients with advanced multiple myeloma. Vaccines composed of purified paraproteins linked to phage were manufactured successfully for each patient.

NK cells from an AML patient have recovered in remission and reached comparable cytolytic activity to that of a healthy monozygotic twin mediated by the single-chain triplebody SPM-2.

Background: The capacity of patient's Natural Killer cells (NKs) to be activated for cytolysis is an important prerequisite for the success of antibody-derived agents such as single-chain triplebodies (triplebodies) in cancer therapy. NKs recovered from AML patients at diagnosis are often found to be reduced in peripheral blood titers and cytolytic activity. Here, we had the unique opportunity to compare blood titers and cytolytic function of NKs from an AML patient with those of a healthy monozygotic twin.

Chemically linked phage idiotype vaccination in the murine B cell lymphoma 1 model.

Background: B cell malignancies are characterized by clonal expansion of B cells expressing tumor-specific idiotypes on their surface. These idiotypes are ideal target antigens for an individualized immunotherapy. However, previous idiotype vaccines mostly lacked efficiency due to a low immunogenicity of the idiotype.

A dual-targeting triplebody mediates preferential redirected lysis of antigen double-positive over single-positive leukemic cells.

The single-chain triplebody HLA-ds16-hu19 consists of three single-chain Fv (scFv) antibody fragments connected in a single polypeptide chain. This protein with dual-targeting capacity mediated preferential lysis of antigen double positive(dp) over single-positive (sp) leukemic cells by recruitment of natural killer (NK) cells as effectors. The two distal scFv modules were specific for the histocompatibility protein HLA-DR and the lymphoid antigen CD19, the central one for the Fc gamma receptor CD16.

Incidence and risk factors of bisphosphonate-related osteonecrosis of the jaw in multiple myeloma patients having undergone autologous stem cell transplantation.

Background: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe complication of bisphosphonate therapy. Due to their long survival and subsequently high cumulative doses of bisphosphonates, multiple myeloma patients have the highest risk of developing BRONJ of all patients treated with bisphosphonates. The purpose of the present study was to evaluate the incidence and risk factors for BRONJ in multiple myeloma patients after high-dose chemotherapy and autologous stem cell transplantation (ASCT).

Priority-setting, rationing and cost-effectiveness in the German health care system.

Germany has just started a public debate on priority-setting, rationing and cost-effectiveness due to the cost explosion within the German health care system. To date, the costs for German health care run at 11,6% of its Gross Domestic Product (GDP, 278,3 billion €) that represents a significant increase from the 5,9 % levels present in 1970. In response, the German Parliament has enacted several major and minor legal reforms over the last three decades for the sake of cost containment and maintaining stability of the health care system.

A recombinant triplebody with specificity for CD19 and HLA-DR mediates preferential binding to antigen double-positive cells by dual-targeting.

To test the hypothesis that dual-targeting confers the novel ability of selective binding to antigen double-positive over antigen single-positive cells, a single-chain triplebody (sctb), HLA-ds16-hu19, was produced and characterized. The molecule carries three single-chain Fv (scFv) antibody fragments in a single polypeptide chain, the two distal ones specific for the human histocompatibility protein HLA-DR and the B-lymphoid cell surface protein CD19, the central one for CD16, the human low affinity Fc-receptor FcγRIII. For comparison, the bispecific scFvs (bsscFv) hu19-ds16 and HLA-ds16 were also produced.

The pan-histone deacetylase inhibitor CR2408 disrupts cell cycle progression, diminishes proliferation and causes apoptosis in multiple myeloma cells.

In view of the fact that histone deacetylases (HDACs) are promising targets for myeloma therapy, we investigated the effects of the HDAC inhibitor CR2408 on multiple myeloma (MM) cells in vitro. CR2408 is a direct pan-HDAC inhibitor and inhibits all known 11 HDACs with a 50% inhibitory concentration (IC(50) ) of 12 nmol/l (HDAC 6) to 520 nmol/l (HDAC 8). Correspondingly, CR2408 induces hyperacetylation of histone H4, inhibits cell growth and strongly induces apoptosis (IC(50) =0.