Broadening the horizon: potential applications of CAR-T cells beyond current indications.

Engineering immune cells to treat hematological malignancies has been a major focus of research since the first resounding successes of CAR-T-cell therapies in B-ALL. Several diseases can now be treated in highly therapy-refractory or relapsed conditions. Currently, a number of CD19- or BCMA-specific CAR-T-cell therapies are approved for acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), multiple myeloma (MM), and follicular lymphoma (FL). The implementation of these therapies has significantly improved patient outcome and survival even in cases with previously very poor prognosis. In this comprehensive review, we present the current state of research, recent innovations, and the applications of CAR-T-cell therapy in a selected group of hematologic malignancies. We focus on B- and T-cell malignancies, including the entities of cutaneous and peripheral T-cell lymphoma (T-ALL, PTCL, CTCL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), classical Hodgkin-Lymphoma (HL), Burkitt-Lymphoma (BL), hairy cell leukemia (HCL), and Waldenström's macroglobulinemia (WM). While these diseases are highly heterogenous, we highlight several similarly used approaches (combination with established therapeutics, target depletion on healthy cells), targets used in multiple diseases (CD30, CD38, TRBC1/2), and unique features that require individualized approaches. Furthermore, we focus on current limitations of CAR-T-cell therapy in individual diseases and entities such as immunocompromising tumor microenvironment (TME), risk of on-target-off-tumor effects, and differences in the occurrence of adverse events. Finally, we present an outlook into novel innovations in CAR-T-cell engineering like the use of artificial intelligence and the future role of CAR-T cells in therapy regimens in everyday clinical practice.

[Splenic surgery in hematological diseases : Indications and surgical technique]. / Chirurgie der Milz bei hämatologischen Erkrankungen : Indikationen und operative Technik.

BACKGROUND: Splenic surgery in hematological disorders requires a well-weighted decision on the indications because the medical treatment has rapidly changed in recent years due to new pharmaceutical approaches. OBJECTIVE: Summary of the indications, surgical procedures and perioperative management regarding operative interventions on the spleen in hematological disorders. MATERIAL AND METHODS: Selective literature search and summary of reviews and guideline recommendations. RESULTS: In hematological disorders surgical procedures of the spleen (splenectomy and partial splenectomy) are an important part of the repertoire in the treatment. In recent years the indications for surgery have become narrower because of new forms of medicinal treatment. Especially in hereditary spherocytosis, immune thrombocytopenia and symptomatic splenomegaly and hypersplenism it is still of importance. The minimally invasive splenectomy is regarded as the gold standard. The spleen has an important immune and sequestration function, therefore preoperative and postoperative infectious and thromboembolic events have to be anticipated and prevented. A close interdisciplinary cooperation with hematologists is essential for an optimal outcome of patients. CONCLUSION: The minimally invasive splenectomy and partial splenectomy are part of the surgical repertoire in the diagnostics and treatment of hematological disorders. Because of novel medicinal approaches the therapeutic protocols are continuously changing. A close cooperation with hematologists is important for the optimal evaluation of the indications and the perioperative management.

Targeted hyperactivation of AKT through inhibition of ectopic expressed SHIP1 induces cell death in colon carcinoma cells and derived metastases.

Current therapeutic approaches for colorectal cancer (CRC) focus on the suppression of oncogenic kinase signaling. Here, we test the hypothesis that targeted hyperactivation of the PI3K/AKT-signaling may lead to trigger CRC cell death. Recently we found that hematopoietic SHIP1 is ectopically expressed in CRC cells. Here we show that SHIP1 is more strongly expressed in metastatic cells than in the primary cancer cells, which allows for an increase in AKT signaling in metastatic cells, giving them an advantage from an evolutionary point of view. Mechanistically, the increased SHIP1 expression reduces the activation of the PI3K/ AKT signaling to a value that is below the threshold that leads to cell death. This mechanism gives the cell a selection advantage. We show that genetic hyperactivation of PI3K/AKT-signaling or blocking the activity of the inhibitory phosphatase SHIP1, induces acute cell death in CRC cells, because of excessive accumulation of reactive oxygen species. Our results demonstrate that CRC cells critically depend on mechanisms to fine-tune PI3K/AKT activity and show SHIP1 inhibition as an unexpectedly promising concept for CRC therapy.

Epidemiology and Characteristics of Gastric Carcinoma in Childhood-An Analysis of Data from Population-Based and Clinical Cancer Registries.

(1) Background: Gastric carcinoma is an exceptionally rare tumor in childhood. Little is known about the etiology, epidemiology, and clinical features of pediatric gastric carcinomas. This analysis aimed to fill this gap by increasing knowledge about the occurrence of gastric carcinoma in childhood. (2) Material and methods: Data from gastric carcinoma cases diagnosed between 2000 and 2017/2018 were retrieved from the Surveillance, Epidemiology, and End Results Program (SEER) and the German Center for Cancer Registry Data. Data from patients <20 years of age were analyzed for patient- and tumor-related characteristics. In addition, clinical data from patients with gastric carcinoma registered in the German Registry for Rare Pediatric Tumors (STEP) were analyzed for diagnostics, therapy, and outcome. (3) Results: Ninety-one cases of gastric carcinoma, mainly in adolescents, were identified in the epidemiologic cancer registries. Among patients with recorded staging data, advanced tumor stages were common (66.7%). Within the follow-up period covered, 63.7% of patients with clinical follow-up data died. Eight pediatric patients with gastric carcinoma were enrolled in the STEP registry, among whom two were patients with hereditary CDH1 mutations and another was a patient with Peutz−Jeghers syndrome. Three patients were found to have distinctly decreased immunoglobulin concentrations. All four patients in whom complete resection was achieved remained in remission. Three of the other four patients died despite multimodal therapy. (4) Conclusions: A combination of Helicobacter pylori infection and tumor predisposition and/or immunodeficiency appears to promote the development of gastric carcinoma in childhood. While patients with localized disease stages have a good chance of achieving durable remission through complete resection, patients with stage IV carcinomas face a dismal prognosis, highlighting the need to develop new strategies such as mutation-guided treatments.

Tumor cell E-selectin ligands determine partialefficacy of bortezomib on spontaneous lung metastasis formation of solid human tumors in vivo.

Extravasation of circulating tumor cells (CTCs) is critical for metastasis and is initiated by adhesive interactions between glycoligands on CTCs and E-selectin on endothelia. Here, we show that the clinically approved proteasome inhibitor bortezomib (BZM; Velcade) counteracts the cytokine-dependent induction of E-selectin in the lung mediated by the primary tumor, thereby impairing endothelial adhesion and thus spontaneous lung metastasis in vivo. However, the efficacy of BZM crucially depends on the tumor cells' E-selectin ligands, which determine distinct adhesion patterns. The canonical ligands sialyl-Lewis A (sLeA) and sLeX mediate particularly high-affinity E-selectin binding so that the incomplete E-selectin-reducing effect of BZM is not sufficient to disrupt adhesion or metastasis. In contrast, tumor cells lacking sLeA/X nevertheless bind E-selectin, but with low affinity, so that adhesion and lung metastasis are significantly diminished. Such low-affinity E-selectin ligands apparently consist of sialylated MGAT5 products on CD44. BZM no longer has anti-metastatic activity after CD44 knockdown in sLeA/X-negative tumor cells or E-selectin knockout in mice. sLeA/X can be determined by immunohistochemistry in cancer samples, which might aid patient stratification. These data suggest that BZM might act as a drug for inhibiting extravasation and thus distant metastasis formation in malignancies expressing low-affinity E-selectin ligands.

Clinical evaluation of a novel head protection system for interventional radiologists.

PURPOSE: A novel two-part protective system consisting of a modified thyroid collar and a head protection is intended to reduce the radiation dose to the examiners head during fluoroscopy-guided interventions. In this pilot study, we tested this protection system under real-life conditions in general radiological and neuroradiological interventions. METHODS: Two sets of the protection system (set A and B) were equipped with 12 thermoluminiscence detectors (TLD). For simultaneous measurement of radiation exposure and dose-reduction, each six TLDs were fixed to the inner side and on the corresponding outer side of the protection system. Set A was used exclusively for general radiological interventions and set B exclusively for neuroradiological interventions. To compare the staff exposure in general radiology and neuroradiology, dose values were normalized to a DAP of 10 000 µGy∙m2. RESULTS: The sets were tested during 20 general radiological interventions and 32 neuroradiological interventions. In neuroradiology, the mean normalized radiation exposure was 13.44 ± 1.36 µSv/10000 µGy∙m2 at the head protection and 22.27 ± 2.09 µSv/10 000 µGy∙m2 at the thyroid collar. In general radiology, the corresponding results were 29.91 ± 4.19 µSv/10 000 µGy∙m2 (head protection) and 68.07 ± 17.25 µSv/10 000 µGy∙m2 (thyroid collar). Thus, mean dose exposure was 2.5 times higher in general radiological interventions (p = 0.016). The use of the protection system resulted in a mean dose reduction of 81.2 ± 11.1 % (general radiology) and 92.1 ± 4.2 % (neuroradiology; p = 0.016). CONCLUSION: Fluoroscopy-guided interventions lead to significant radiation exposure of the head area for the examiner. The novel protection system tested led to a significant dose reduction of 80-90%, depending on the type of intervention.

Combined Targeting of AKT and mTOR Synergistically Inhibits Formation of Primary Colorectal Carcinoma Tumouroids In Vitro: A 3D Tumour Model for Pre-therapeutic Drug Screening.

BACKGROUND: Pre-therapeutic analysis of three-dimensional spheroid cultures of primary tumour samples is a promising approach of assessing susceptibility to potential treatment. The phosphatidylinositol-3-kinase/AKT serine/threonine kinase/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway is frequently activated in colorectal cancer (CRC). In previous work, we showed combined inhibition of AKT and mTOR to be highly synergistic in cell lines from patients with hepatocellular carcinoma and cholangiocarcinoma in vitro as well as in vivo in murine xenograft tumour models. MATERIALS AND METHODS: Patient-derived xenograft colorectal carcinoma cell lines HROC80 T1 M1, HROC147 T0 M1, HROC147Met, HROC277 T0 M1 and HROC277Met2 were treated with AKT inhibitor MK2206, mTOR inhibitor RAD001 or the combination of both drugs. The sensitivity of these cell lines to inhibition was evaluated by calculation of combinatory indices after bromodeoxyuridine assays and analysis of the respective pathways by western blotting. Furthermore, the dual inhibition of AKT and mTOR was confirmed in vivo in a xenograft mouse model. Additionally, primary CRC samples of four patients were embedded in a three-dimensional matrix and the sensitivity of these samples was analyzed by measurement of the spheroid area. RESULTS: In this study, we demonstrate that combined treatment with MK2206 and RAD001 resulted in strong synergistic effects on growth of several primary CRC cell lines and reduced the growth of a patient-derived CRC xenograft in a xenotransplantation mouse model in vivo. Interestingly, the response to treatment varied between cell lines derived from the primary lesion and a liver metastasis of the same patient. In addition, combined treatment with AKT and mTOR inhibitors resulted in a synergistic inhibition of tumouroid growth in all four of the primary patient samples, analyzed in a three-dimensional spheroid model in vitro. CONCLUSION: Our data demonstrate that combined treatment with AKT and mTOR inhibitors exhibits synergistic effects on proliferation of cell lines and primary tumour cells from patients with CRC and may be a promising approach for the treatment of CRC.

Prenatal radiation exposure in diagnostic and interventional radiology. / Pränatale Strahlenexposition in der diagnostischen und interventionellen Radiologie.

BACKGROUND: The exposure of a pregnant woman to X-rays is an event that can cause uncertainty for all concerned. This review provides guidance on how to assess such a situation and how to determine the dose to the unborn child. In general, the use of X-rays in pregnant women in radiology should be avoided. If possible, alternatives should be used, or examinations postponed to a time after the pregnancy. This review gives a summary of the procedure for determining the radiation exposure of a pregnant woman. METHOD: Based on the previous report of 2002 and the literature on prenatal radiation exposure published thereafter, the DGMP/DRG report on the procedure for the assessment of prenatal radiation exposure was adapted to the current state of science and technology. RESULTS: Typically, only relatively low radiation exposures of less than 20 mSv occur for the unborn child in X-ray diagnostics in the vast majority of cases. At these dose level the additional risk of damage to the embryo or fetus caused by the radiation is low and therefore only a rough conservative estimate using tabulated values are made. Only in a few types of examination (CT and interventional radiology) higher doses values might occur in the uterus. Instead of dose estimates (step 1 in the two-step model) in these cases the calculation of dose (step 2) are required and further action by the physician may be necessary. CONCLUSIONS: During the assessment, it is useful to initially use simple conservative estimation procedures to quickly determine whether a case falls into this large group less than 20 mSv, where there is a very low risk to the unborn child. If this is the case, the pregnant woman should be informed immediately by the doctor who performed the examination/treatment. This avoids a psychological burden on the patient. The DGMP/DRG report suggests a relatively simple, clearly structured procedure with advantages for all parties involved (physician, medical physics experts, MTRA and patient). KEY POINTS: · The DGMP/DRG report on prenatal radiation exposure describes the procedure for calculating radiation exposures and the associated risks for the unborn child.. · Using the two-step model, only a simple assessment based on the first step is necessary for most prenatal radiation exposures.. · With the given tables it is possible to estimate individual risks for the unborn child taking into account the radiation exposure.. · Only in the rare case that the first estimate results in a uterine dose larger 20 mSv a more accurate calculation is necessary.. CITATION FORMAT: · Fiebich M, Block A, Borowski M et al. Prenatal radiation exposure in diagnostic and interventional radiology. Fortschr Röntgenstr 2021; 193: 778 - 786.

Implications of SARS-CoV-2 Infection and COVID-19 Crisis on Clinical Cancer Care: Report of the University Cancer Center Hamburg.

With the outbreak of the COVID-19 pandemia, routine clinical work was immediately, deeply, and sustainably impacted in Germany and worldwide. The infrastructure of almost all hospitals is currently redirected to provide a maximum of intensive care resources, including the necessary staff. In parallel, routine as well as emergency clinical care for all patients in need has to be secured. This challenge becomes particularly evident in cancer care. In order to maintain adequate oncological care at all levels of provision and to conduct especially curative and intensive treatments with a maximum of safety, continuous adaption of the oncology care system has to be ensured. Intensive communication with colleagues and patients is needed as is consequent expert networking and continuous reflection of the own developed strategies. In parallel, it is of high importance to actively avoid cessation of innovation in order not to endanger the continuous improvement in prognosis of cancer patients. This includes sustained conduction of clinical trials as well as ongoing translational research. Here, we describe measures taken at the University Cancer Center Hamburg (UCCH) - a recognized comprehensive oncology center of excellence - during the COVID-19 crisis. We aim to provide support and potential perspectives to generate a discussion basis on how to maintain high-end cancer care during such a crisis and how to conduct patients safely into the future.

Case report: acute abdominal pain in a 37-year-old patient and the consequences for his family.

BACKGROUND: Hereditary diffuse gastric cancer is a rare condition that accounts for approximately 1-3% of all gastric cancer cases. Due to its rapid and invasive growth pattern, it is associated with a very poor prognosis. As a result, comprehensive genetic testing is imperative in patients who meet the current testing criteria in order to identify relatives at risk. This case report illustrates the substantial benefit of genetic testing in the family of a patient diagnosed with hereditary diffuse gastric cancer. CASE PRESENTATION: A 37-year-old patient was admitted to the emergency department with acute abdominal pain. Following explorative laparoscopy, locally advanced diffuse gastric cancer was diagnosed. The indication for genetic testing of CDH1 was given due to the patient's young age. A germline mutation in CDH1 was identified in the index patient. As a result, several family members underwent genetic testing. The patient's father, brother and one aunt were identified as carriers of the familial CDH1 mutation and subsequently received gastrectomy. In both the father and the aunt, histology of the surgical specimen revealed a diffuse growing adenocarcinoma after an unremarkable preoperative gastroscopy. CONCLUSION: Awareness and recognition of a potential hereditary diffuse gastric cancer can provide a substantial health benefit not only for the patient but especially for affected family members.

Technical Note: Accuracy of MTF measurements with an edge phantom at megavoltage x-ray energies.

PURPOSE: Measurement of the modulation transfer function (MTF) is performed by evaluating the response of an imaging system to a predefined input. To obtain accurate results when using an edge phantom, the detector input signal must resemble an ideal step function. The MTF of megavoltage (MV) imagers used in radiotherapy has been measured with highly absorbing edge phantoms fabricated from thick metal blocks. This study investigates the influence of the edge phantom design on the accuracy of the resulting MTF. METHODS: The MTF of an electronic portal imaging device (EPID) was measured at 6 MV beam quality with four edge phantoms made of lead with 1.3, 3.3, 5.0, and 10.0 cm thickness. Monte Carlo simulations were carried out for these and a selection of tungsten phantoms to determine the photon fluence at the imaging plane and quantify the systematic error in the MTF introduced by the edge phantom design. RESULTS: The measured MTF depends on the design of the edge phantom. The detector input signal of a thin phantom is affected by secondary radiation from the phantom itself, causing an overestimation of the MTF. The amount of secondary radiation can be reduced by increasing the phantom thickness or introducing an air gap between the phantom and the detector. Both methods introduce geometric unsharpness, which can result in an underestimation of the true MTF. Edge phantoms made from 4.0 cm thick tungsten or 5.0 cm thick lead induce comparatively small systematic errors of below 3% or 5%, respectively. CONCLUSIONS: When MTF measurements are conducted at MV energies, even a highly absorbing edge phantom will introduce a systematic error of several percent. Direct comparison of MTFs obtained with different edge phantoms should therefore be treated with caution.

Investigation of Radiation Exposure of Patients with Acute Ischemic Stroke during Mechanical Thrombectomy. / Untersuchung der Strahlenexposition des Patienten mit akutem ischämischem Schlaganfall während der mechanischen Thrombektomie.

PURPOSE: In radiological interventions, the skin is the most exposed organ. The aim of this study was to investigate the local dose exposure and the resulting risk of deterministic radiation effects for patients who underwent mechanichal thrombectomy. MATERIALS AND METHODS: The examination protocols of 50 consecutive stroke patients who underwent mechanical thrombectomy from September 2016 to April 2017 were evaluated in this study. All procedures were performed on a biplanar angiographic suite. The local skin equivalent dose H P(0.07) was calculated retrospectively using the recorded radiation data and previously measured conversion factors. The in-vitro determination of the conversion factors was performed with a silicon semiconductor detector on the surface of an Alderson-Rando head phantom depending on the radiation quality. RESULTS: Vessel occlusion was located in the M1 and M2 segments of the cerebral artery media (n = 32), the internal carotid artery or carotid-T (n = 12) and the basilar artery (n = 6). The fluoroscopy times ranged from 5.7 minutes to 137.3 minutes with an average value of 39.5 ±â€Š4.1 minutes. The determined skin equivalent dose values ranged from 0.16 ±â€Š0.02 Gy to 4.80 ±â€Š0.51 Gy, with the mean value being 1.00 ±â€Š0.14 Gy. In 3 out of 50 cases (6 %), the threshold value for skin reactions of 3 Gy published by the German Radiation Protection Commission was exceeded. A further 15 patients (36 %) were exposed to a dose of 1-3 Gy. The highest dose values were achieved during long procedures with occlusions in the posterior circulation and carotid occlusions. In addition, a local dose reference level of 1.24 ±â€Š0.15 Gy could be determined for the skin equivalent dose in mechanical thrombectomies for our center. CONCLUSION: Even during a modern neuroradiological intervention, such as mechanical thrombectomy, radiation doses to the patient are produced and can lead to deterministic radiation damage to the skin in approximately 6 % of cases. Systematic monitoring of local dose quantities, such as H P(0.07), seems appropriate. Possibilities for recording and reducing the local dose load should be developed by the interventional teams in cooperation with a medical physics expert. KEY POINTS: · In 64 % of the thrombectomies the skin equivalent doses were in the harmless range (< 1 Gy).. · In 6 % of the patients higher H P(0.07) values were determined, which can lead to deterministic radiation damage to the skin.. · To avoid deterministic damage during neurointerventions, H P(0.07) should be recorded (combined measuring chambers).. · For longer interventions, precautions should be taken to reduce the radiation dose.. CITATION FORMAT: · Bärenfänger F, Block A, Rohde S. Investigation of Radiation Exposure of Patients with Acute Ischemic Stroke during Mechanical Thrombectomy. Fortschr Röntgenstr 2019; 191: 1099 - 1106.

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/m2 epirubicin and 60 mg/m2 cisplatin on day 1 plus either 200 mg/m2 fluorouracil as continuous intravenous infusion or 1250 mg/m2 capecitabine orally on days 1 to 21 (ECF/ECX; control group) or four preoperative and four postoperative 2-week cycles of 50 mg/m2 docetaxel, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin and 2600 mg/m2 fluorouracil as 24-h infusion on day 1 (FLOT; experimental group). The primary outcome of the trial was overall survival (superiority) analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01216644. FINDINGS: Between Aug 8, 2010, and Feb 10, 2015, 716 patients were randomly assigned to treatment in 38 German hospitals or with practice-based oncologists. 360 patients were assigned to ECF/ECX and 356 patients to FLOT. Overall survival was increased in the FLOT group compared with the ECF/ECX group (hazard ratio [HR] 0·77; 95% confidence interval [CI; 0.63 to 0·94]; median overall survival, 50 months [38·33 to not reached] vs 35 months [27·35 to 46·26]). The number of patients with related serious adverse events (including those occurring during hospital stay for surgery) was similar in the two groups (96 [27%] in the ECF/ECX group vs 97 [27%] in the FLOT group), as was the number of toxic deaths (two [<1%] in both groups). Hospitalisation for toxicity occurred in 94 patients (26%) in the ECF/ECX group and 89 patients (25%) in the FLOT group. INTERPRETATION: In locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma, perioperative FLOT improved overall survival compared with perioperative ECF/ECX. FUNDING: The German Cancer Aid (Deutsche Krebshilfe), Sanofi-Aventis, Chugai, and Stiftung Leben mit Krebs Foundation.

PICCA study: panitumumab in combination with cisplatin/gemcitabine chemotherapy in KRAS wild-type patients with biliary cancer-a randomised biomarker-driven clinical phase II AIO study.

BACKGROUND: Combination chemotherapy has shown benefit in the treatment of biliary cancer and further improvements might be achieved by the addition of a biological agent. We report here the effect of chemotherapy with the monoclonal EGFR antibody panitumumab as therapy for KRAS wild-type biliary cancer. PATIENTS AND METHODS: Patients with advanced biliary tract cancer were randomised (2:1) to receive cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 on day 1 and day 8/q3w with (arm A) or without panitumumab (arm B; 9 mg/kg BW, i.v q3w). The primary end-point was the evaluation of progression-free survival (PFS) at 6 months. Secondary end-points included objective response rate (ORR), overall survival (OS), and toxicity. In addition, a post hoc assessment of genetic alterations was performed. Finally, we performed a meta-analysis of trials with chemotherapy with and without EGFR antibodies. RESULTS: Sixty-two patients were randomised in arm A and 28 patients in arm B. Patients received 7 treatment cycles in median (1-35) with a median treatment duration of 4.7 months (141 days, 8-765). PFS rate at 6 months was 54% in patients treated with cisplatin/gemcitabine and panitumumab but was 73% in patients treated with cisplatin/gemcitabine without antibody, respectively. Secondary end-points were an ORR of 45% in treatment arm A compared with 39% receiving treatment B and a median OS of 12.8 months (arm A) and of 20.1 months (arm B), respectively. In contrast to the p53-status, genetic alterations in IDH1/2 were linked to a high response after chemotherapy and prolonged survival. In accordance with our results, the meta-analysis of 12 trials did not reveal a survival advantage for patients treated with EGFR antibodies compared with chemotherapy alone. CONCLUSIONS: Panitumumab in combination with chemotherapy does not improve ORR, PFS and OS in patients with KRAS wild-type, advanced biliary cancer. Genetic profiling should be included in CCA trials to identify and validate predictive and prognostic biomarkers. CLINICAL TRIALS NUMBER: The trial was registered with NCT01320254.

CabaGast: multicentre, Phase II study with cabazitaxel in previously treated patients with advanced or metastatic adenocarcinoma of the esophagogastric junction and stomach.

INTRODUCTION: This is a single-arm study (NCT01956149) to determine the prolonged (≥ 4 months) disease control rate with cabazitaxel administered in second-(or later) setting for patients with advanced or metastatic adenocarcinoma of the esophagogastric junction (EGJ) and stomach. METHODS: 65 patients with advanced EGJ and stomach cancer were treated with 20 mg/m2 cabazitaxel every 3 weeks for a maximum of six cycles. The main objective of the study is a prolonged disease control rate (pDCR: CR, PR or SD lasting at least 4 months). Secondary outcome measures were overall survival, progression-free survival, response rate by subgroup (with vs without previous treatment with a taxane) and toxicity. Patients were assessed for tumor response every 6 weeks during therapy and during the follow-up (up to 12 months). RESULTS: 65 patients (median age: 63, range 31-86 years) were assigned to treatment. Median no. of prior therapies that had received prior taxane therapy was 2. 80%. Patients received a median of two cycles of cabazitaxel. Efficacy results are for the ITT population. The mDCR in n = 65 patients was 10.8% (95% CI 4.4-20.9%). There was a control of disease (CR + PR + SD) in n = 26 patients of n = 65, corresponding to a DCR of 40.0% (95% CI 28.0-52.9%). In patients without prior taxane use, it was 46.2% (95% CI 25.1-80.8%) and in patients with only one prior therapy, DCR was 50.0% (95% CI 31.3-68.7%). The median overall survival was 4.6 months (95% CI 3.16, 5.59) in the whole ITT population. In patients with only one prior therapy, median OS was 5.4 months (95% CI 2.60, 7.43) and in patients without taxane pretreatment, it was 6.4 months (95% CI 1.38, 14.17). The median progression-free survival time was 1.5 months (95% CI 1.32, 2.27) in the whole ITT population, 2.9 months (95% CI 0.72, 4.67) without prior taxane therapy and was 1.7 (95% CI 1.28, 3.35) months in patients with only one prior therapy median. CONCLUSIONS: Cabazitaxel is active in heavily pretreated patients with metastatic and advanced esophagogastric junction and gastric adenocarcinoma. Efficacy results in a classic second-line population are comparable to other second-line studies, therefore, under the limitations of this trial, (single arm, Phase II design) cabazitaxel might be an option especially in patients without prior taxane therapy, in second line and even further line therapy of metastatic and advanced esophagogastric junction and gastric adenocarcinoma.

Intercenter validation of a knowledge based model for automated planning of volumetric modulated arc therapy for prostate cancer. The experience of the German RapidPlan Consortium.

PURPOSE: To evaluate the performance of a model-based optimisation process for volumetric modulated arc therapy applied to prostate cancer in a multicentric cooperative group. The RapidPlan (RP) knowledge-based engine was tested for the planning of Volumetric modulated arc therapy with RapidArc on prostate cancer patients. The study was conducted in the frame of the German RapidPlan Consortium (GRC). METHODS AND MATERIALS: 43 patients from one institute of the GRC were used to build and train a RP model. This was further shared with all members of the GRC plus an external site from a different country to increase the heterogeneity of the patient's sampling. An in silico multicentric validation of the model was performed at planning level by comparing RP against reference plans optimized according to institutional procedures. A total of 60 patients from 7 institutes were used. RESULTS: On average, the automated RP based plans resulted fully consistent with the manually optimised set with a modest tendency to improvement in the medium-to-high dose region. A per-site stratification allowed to identify different patterns of performance of the model with some organs at risk resulting better spared with the manual or with the automated approach but in all cases the RP data fulfilled the clinical acceptability requirements. Discrepancies in the performance were due to different contouring protocols or to different emphasis put in the optimization of the manual cases. CONCLUSIONS: The multicentric validation demonstrated that it was possible to satisfactorily optimize with the knowledge based model patients from all participating centres. In the presence of possibly significant differences in the contouring protocols, the automated plans, though acceptable and fulfilling the benchmark goals, might benefit from further fine tuning of the constraints. The study demonstrates that, at least for the case of prostate cancer patients, it is possibile to share models among different clinical institutes in a cooperative framework.

Novel biomarkers in cancer: The whole is greater than the sum of its parts.

The major issues hampering progress in the treatment of cancer patients are distant metastases and drug resistance to chemotherapy. Metastasis formation is a very complex process, and looking at gene signatures alone is not enough to get deep insight into it. This paper reviews traditional and novel approaches to identify gene signature biomarkers and intratumoural fluid pressure both as a novel way of creating predictive markers and as an obstacle to cancer therapy. Finally recently developed in vitro systems to predict the response of individual patient derived cancer explants to chemotherapy are discussed.

Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial.

BACKGROUND: Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma, but has not yet been evaluated in the context of resectable patients. Here we report findings from the phase 2 part of the phase 2/3 FLOT4 trial, which compared histopathological regression in patients treated with a docetaxel-based triplet chemotherapy versus an anthracycline-based triplet chemotherapy before surgical resection. METHODS: In this randomised, open-label, phase 2/3 study, eligible participants were recruited from 28 German oncology centres. Patients with resectable gastric or gastro-oesophageal junction cancer who had clinical stage cT2 or higher, nodal positive (cN+) disease, or both were randomly assigned (1:1) to either three preoperative and three postoperative 3-week cycles of intravenous epirubicin 50 mg/m2 on day 1, intravenous cisplatin 60 mg/m2 on day 1, and either fluorouracil 200 mg/m2 as continuous intravenous infusion or capecitabine 1250 mg/m2 orally (two doses of 625 mg/m2 per day) on days 1 to 21 (ECF/ECX group) or four preoperative and four postoperative 2-week cycles of docetaxel 50 mg/m2, intravenous oxaliplatin 85 mg/m2, intravenous leucovorin 200 mg/m2, and fluorouracil 2600 mg/m2 as a 24 h infusion, all on day 1 (FLOT group). Randomisation was done centrally with an interactive web-response system based on a sequence generated with blocks (block size 2) stratified by Eastern Cooperative Oncology Group performance status, location of primary tumour, age, and nodal status. No masking was done. Central assessment of pathological regression was done according to the Becker criteria. The primary endpoint was pathological complete regression (tumour regression grade TRG1a) and was analysed in the modified intention-to-treat population, defined as all patients who were randomly assigned to treatment excluding patients who had surgery but did not provide resection specimens for central evaluation. The study (including the phase 3 part) has completed enrolment, but follow-up is ongoing and this is an interim analysis. The trial is registered with ClinicalTrials.gov, number NCT01216644. FINDINGS: Between Aug 18, 2010, and Aug 10, 2012, 300 patients (152 patients in the ECF/ECX group; 148 patients in the FLOT group) were enrolled into the phase 2 part of the study, 265 of whom (137 in the ECF/ECX group; 128 in the FLOT group) were assessable on a modified intention-to-treat basis. 119 (93%) of 128 patients in the FLOT group and 126 (92%) of 137 patients in the ECF/ECX group were given all planned preoperative cycles of treatment. FLOT was associated with significantly higher proportions of patients achieving pathological complete regression than was ECF/ECX (20 [16%; 95% CI 10-23] of 128 patients vs eight [6%; 3-11] of 137 patients; p=0·02). 44 (40%) of 111 patients in the ECF/ECX group and 30 (25%) of 119 patients in the FLOT group had at least one serious adverse event involving a perioperative medical or surgical complication. The most common non-surgical grade 3-4 adverse events were neutropenia (52 [38%] of 137 patients in the ECF/ECX group vs 67 [52%] of 128 patients in the FLOT group), leucopenia (28 [20%] vs 36 [28%]), nausea (23 [17%] vs 12 [9%]), infection (16 [12%] vs 15 [12%]), fatigue (19 [14%] vs 11 [9%]), and vomiting (13 [10%] vs four [3%]). INTERPRETATION: Perioperative FLOT was active and feasible to administer, and might represent an option for patients with locally advanced, resectable gastric or gastro-eosophageal junction adenocarcinoma. FUNDING: None.