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P1 oncogenerative cell division as a whole cell entity is shown here.

The effects of anticancer treatments on cell heterogeneity and their proliferative potential play an important role in tumor persistence and metastasis. However, little is known about de-polyploidization, cell fate, and physiologic stemness of the resulting cell populations. Here, we describe a distinctive cell type termed "pregnant" P1 cells found within chemotherapy-refractory ovarian tumors, which generate and gestate daughter generation Gn cells intracytoplasmically. Release of Gn cells occurred by ejection through crevices in the P1 cell membrane by body contractions or using a funiculus-like structure. These events characterized a not yet described mechanism of cell segregation. Maternal P1 cells were principally capable of surviving parturition events and continued to breed and nurture Gn progenies. In addition, P1 cells were competent to horizontally transmit offspring Gn cells into other specific proximal cells, injecting them to receptor R1 cells via cell–cell tunneling. This process represents a new mechanism used by tumor cells to invade surrounding tissues and ensure life cycles. In contrast to the pregnant P1 cells with low expression of stem cell markers despite their physiologic stemness, the first offspring generations of daughter G1 cells expressed high levels of ovarian cancer stem cell markers. Furthermore, both P1 and Gn cells overexpressed multiple human endogenous retroviral envelope proteins. Moreover, programmed death-ligand 1 and the immunosuppressive domain of the retroviral envelope proteins were also overexpressed in P1 cells, suggesting effective protection against the host immune system. Together, our data suggest that P1 oncogenerative cancer cells exhibit a not yet described cell biological mechanism of persistence and transmission of malignant cells in patients with advanced cancers.Significance: P1 oncogenerative cell entities express low levels of CSC markers, which are characteristic of their histological origin. Cancer Res; 78(9); 2318–31. ©2018 AACR.

P1 cells seem to undergo divisions in to similar oncogenerative cells by cytoplasm separation. The process is in par orchestrated with the participation of mitochondria which delimitate boundaries of cytoplasms to be separated. After this, it is possible to observe a directional cytokinesis like separation of multinucleated cells.

Expression of CSC markers and morphology of P1 oncogenerative and G1-Gn cells as detected by ICC and IHC.

P1 reconstruction in 3D horizontal projection from TEM sections superposed. The inner structure of G1-containing cells is shown.

Replicative elements found in P1 and G1 cells and the expression of HERV envelope proteins in small G1-G2 cells can be visualised here.

P1 oncogenerative cells undergo long quiescent phases in which they do not appear to generate and eject G1 cells.

Resistance profile and spherogenicity of SKOV3 ovarian carcinoma models.

Oncogenerative P1 cells are giant cells with a syncytium-like morphology. This distinctive cell type complete cell life cycles which resemble lysogenic viral cycles. The mode of cellularization of the intracytoplasmically generated G1 cells (generation 1) is unique and takes place in different ways: a) in a lateral form which means that the G1 cells abandon the maternal P1 cells by trans cytoplasmic budding, b) through crevices formed with the participation of mitochondria around G1s until expulsion. After cellularization, the resulted aperture is filled by fusogenic HERV proteins, c) using a kind of funiculus or bridge connected to P1 maternal cells. An interesting process conducted by P1 cells is the horizontal transmission of G1 inoculating these cells into proximal receptor cells.

The lateral separation of G1 from P1 cells is observed in this clip.

The formation of the crevices is observed with the subsequent detachment of G1-Gn cells from mother cytoplasm.

P1 reconstruction in 3D vertical projection from TEM sections superposed. The inner structure of G1-containing cells is shown.

Occurrence and morphology of multinucleated cells in different tumors.

Oncogenerative P1 cells are giant cells with a syncytium-like morphology. This distinctive cell type complete cell life cycles which resemble lysogenic viral cycles. The mode of cellularization of the intracytoplasmically generated G1 cells (generation 1) is unique and takes place in different ways: a) in a lateral form which means that the G1 cells abandon the maternal P1 cells by trans cytoplasmic budding, b) through crevices formed with the participation of mitochondria around G1s until expulsion. After cellularization, the resulted aperture is filled by fusogenic HERV proteins, c) using a kind of funiculus or bridge connected to P1 maternal cells. An interesting process conducted by P1 cells is the horizontal transmission of G1 inoculating these cells into proximal receptor cells.

Expression of CSC markers in multinucleated cells at protein and RNA levels.

This multicenter, randomized phase II/III study evaluated the addition of the vascular endothelial growth factor receptor-2 inhibitor ramucirumab to FLOT as perioperative treatment for resectable esophagogastric adenocarcinoma. Patients received either FLOT alone (Arm A) or combined with ramucirumab followed by ramucirumab monotherapy (Arm B). The primary endpoint for the phase II portion was the pathological complete or subtotal response (pCR/pSR) rate. Baseline characteristics were comparable between both arms with a high rate of tumors signet-ring cell component (A:47% B:43%). No between-arm difference in pCR/pSR rate was seen (A:29% B:26%), therefore the transition to phase III was not pursued. Nevertheless, the combination was associated with a significantly increased R0-resection rate compared to FLOT alone (A:82% B:96%; p=0.009). In addition, the median disease-free survival was numerically improved in Arm B (A:21 months B:32 months, HR 0.75, p=0.218), while the median overall survival was similar in both treatment arms (A:45 months B:46 months, HR 0.94, p=0.803). Patients with Siewert type I tumors receiving transthoracic esophagectomy with intrathoracic anastomosis showed an increased risk of serious postoperative complications after ramucirumab treatment, therefore recruitment of those patients was stopped after the first-third of the study. Overall, surgical morbidity and mortality was comparable, whereas more non-surgical grade≥3 adverse events were observed with the combination, especially anorexia (A:1% B:11%), hypertension (A:4% B:13%) and infections (A:19% B:33%). The combination of ramucirumab and FLOT as perioperative treatment shows efficacy signals, particularly in terms of R0 resection rates, for a study population with a high proportion of prognostically poor histological subtypes, and further evaluation in this subgroup seems warranted. This article is protected by copyright. All rights reserved.

About 8 % of the human genome consists of human endogenous retroviruses (HERVs), which are relicts of ancient exogenous retroviral infections incurred during evolution. Although the majority of HERVs have functional gene defects or epigenetic modifications, many of them are still able to produce retroviral proteins that have been proposed to be involved in cellular transformation and cancer development. We found that, in chemo-resistant U87RETO glioblastoma cells, cytotoxic stress induced by etoposide promotes accumulation and large-scale fission of mitochondria, associated with the detection of HERV-WE1 (syncytin-1) and HERV-FRD1 (syncytin-2) in these organelles. In addition, mitochondrial preparations also contained the corresponding receptors, i.e. ASCT2 and MFSD2. We clearly demonstrated that mitochondria associated with HERV-proteins were shuttled between adjacent cancer cells not only via tunneling tubes, but also by direct cellular uptake across the cell membrane. Furthermore, anti-syncytin-1 and anti-syncytin-2 antibodies were able to specifically block this direct cellular uptake of mitochondria even more than antibodies targeting the cognate receptors. Here, we suggest that the association of mitochondria with syncytin-1/syncytin-2 together with their respective receptors could represent a novel mechanism of cell-tocell transfer. In chemotherapy-refractory cancer cells, this might open up attractive avenues to novel mitochondria-targeting therapies. OA gold

Aim Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is an experimental drug delivery method that applies chemotherapy into the abdominal cavity as an aerosol under pressure. We present the first results obtained with PIPAC in colorectal peritoneal metastasis (CPM). Method This is a retrospective analysis. PIPAC was applied in 17 consecutive patients with pretreated CPM. All patients had previously undergone surgery, and 16 had undergone previous lines of systemic chemotherapy (median, two lines). The mean peritoneal metastasis index (peritoneal cancer index) was 16 ± 10. Forty-eight applications of PIPAC with oxaliplatin (92 mg/m2) were given every 6 weeks at 37°C and 12 mmHg for 30 min. The outcome criteria were microscopic pathological response, survival and adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Results Forty-eight PIPAC administrations were performed with no intra-operative complications. The mean number of PIPAC administrations per patient was 2.8 (minimum one, maximum six). Postoperative adverse events (CTCAE level 3) were observed in four patients (23%), no CTCAE level-4 adverse events were reported. The hospital mortality was zero. Objective tumour responses were observed in 12/17 patients (71%), and the overall responses were as follows: complete pathological response (seven patients), major response (four patients), partial response (one patient), no response (two patients) and not eligible (three patients). The mean survival after first PIPAC was 15.7 months. Conclusion Repeated PIPAC with oxaliplatin can induce the regression of pretreated CPM. The toxicity appears to be low. These preliminary results are encouraging and justify prospective clinical studies.

Background This multicenter, double-blind phase II study assessed the antitumor activity and toxicity profile of docetaxel with the antiangiogenic multikinase inhibitor sorafenib or matching placebo as a first-line treatment in patients with metastatic or locally advanced HER2-negative breast cancer. Patients and methods Patients were randomized 1:1 to receive docetaxel 100 mg/m2 on day 1 every 3 weeks in combination with sorafenib 400 mg bid or placebo on days 2–18 of each cycle until tumor progression, or unacceptable toxicity. Sorafenib/placebo could be continued at the investigator's discretion if docetaxel was stopped due to toxicity. Primary endpoint was progression free survival (PFS). Results From October 2008 to December 2013, 102 patients were randomized; 98 patients were evaluable. The trial was prematurely terminated due to slow accrual. Due to increased toxicity the dose of docetaxel was reduced to 75 mg/m2 and an increasing sorafenib dosing schedule was implemented as part of a protocol amendment. The addition of sorafenib to docetaxel did not improve PFS (8.2 vs. 7.3 months for docetaxel/placebo; HR 0.84, log rank p = 0.43), but led to higher rates of early treatment discontinuation. There were no statistically significant differences between sorafenib dosing schedules. Conclusions Addition of sorafenib to taxane-based first-line chemotherapy in patients with metastatic breast cancer failed to improve PFS and resulted in increased toxicity.

WOS: 000411827200016, PubMed ID: 28961832, Background: This randomized study was designed to investigate the superiority of gemcitabine (gem) plus nimotuzumab (nimo), an anti-epidermal growth factor receptor monoclonal antibody, compared with gem plus placebo as first-line therapy in patients with advanced pancreatic cancer. Patients and methods: Patients with previously untreated, unresectable, locally advanced or metastatic pancreatic cancer were randomly assigned to receive gem: 1000 mg/m(2), 30-min i.v. once weekly (d1, 8, 15; q29) and nimo: fixed dose of 400 mg once weekly as a 30-min infusion, or gem plus placebo, until progression or unacceptable toxicity. The primary end point was overall survival (OS), secondary end points included time to progression, overall response rate, safety and quality of life. Results: A total of 192 patients were randomized, with 186 of them being assessable for efficacy and safety (average age 63.6 years). One-year OS/progression-free survival (PFS) was 34%/22% for gem plus nimo compared with 19%/10% for gem plus placebo (HR = 0.69; P = 0.03/HR = 0.68; P = 0.02). Median OS/PFS was 8.6/5.1 months for gem plus nimo versus 6.0/3.4 mo in the gem plus placebo group (HR = 0.69; P = 0.0341/HR = 0.68; P = 0.0163), with very few grade 3/4 toxicities. KRAS wildtype patients experienced a significantly better OS than those with KRAS mutations (11.6 versus 5.6 months, P = 0.03). Conclusion: This randomized study showed that nimo in combination with gem is safe and well tolerated. The 1-year OS and PFS rates for the entire population were significantly improved. Especially, those patients with KRAS wildtype seem to benefit. The study was registered as protocol ID OSAG101-PCS07, NCT00561990 and EudraCT 2007-000338-38., Oncoscience AG, Schenefeld, Germany, This multi-institutional, randomized phase IIb trial was sponsored by Oncoscience AG, Wedel (recently Schenefeld), Germany. There is no grant number applicable.

Until recently, acquired resistance to cytostatics had mostly been attributed to biochemical mechanisms such as decreased intake and/or increased efflux of therapeutics, enhanced DNA repair, and altered activity or deregulation of target proteins. Although these mechanisms have been widely investigated, little is known about membrane barriers responsible for the chemical imperviousness of cell compartments and cellular segregation in cytostatic-treated tumors. In highly heterogeneous cross-resistant and radiorefractory cell populations selected by exposure to anticancer agents, we found a number of atypical recurrent cell types in (1) tumor cell cultures of different embryonic origins, (2) mouse xenografts, and (3) paraffin sections from patient tumors. Alongside morphologic peculiarities, these populations presented cancer stem cell markers, aberrant signaling pathways, and a set of deregulated miRNAs known to confer both stem-cell phenotypes and highly aggressive tumor behavior. The first type, named spiral cells, is marked by a spiral arrangement of nuclei. The second type, monastery cells, is characterized by prominent walls inside which daughter cells can be seen maturing amid a rich mitochondrial environment. The third type, called pregnant cells, is a giant cell with a syncytium-like morphology, a main nucleus, and many endoreplicative functional progeny cells. A rare fourth cell type identified in leukemia was christened shepherd cells, as it was always associated with clusters of smaller cells. Furthermore, a portion of resistant tumor cells displayed nuclear encapsulation via mitochondrial aggregation in the nuclear perimeter in response to cytostatic insults, probably conferring imperviousness to drugs and long periods of dormancy until nuclear eclosion takes place. This phenomenon was correlated with an increase in both intracellular and intercellular mitochondrial traffic as well as with the uptake of free extracellular mitochondria. All these cellular disorders could, in fact, be found in untreated tumor cells but were more pronounced in resistant entities, suggesting a natural mechanism of cell survival triggered by chemical injury, or a primitive strategy to ensure stemming, self-renewal, and differentiation under adverse conditions, a fact that may play a significant role in chemotherapy outcomes.

Background The aim of this study was the evaluation of pharmacokinetic parameters, biomarkers, clinical outcome, and imaging parameters in metastatic colorectal cancer (mCRC) patients treated with FOLFIRI plus sunitinib. Methods mCRC patients with liver metastases were treated with FOLFIRI and sunitinib as 1st line therapy. At protocol-defined time points, multicontrast magnetic resonance imaging (MRI)measurements, computed tomography (CT) scans, pharmacokinetics (PK), and biomarker analyses were performed during the first and second treatment cycle. Thereafter, patients were treated until tumor progression, investigator’s decision due to toxicity, or patient withdrawal. Results 28 patients were screened, 26 were included, and 23 received at least one study medication. Full safety analysis was performed in 23 patients. Full PK and biomarker analyses were performed in 21 patients. Strong responses in tumor size reduction forced a change from the original imaging timing scheme. This unforeseen change in the timing scheme resulted in subgroups too small for meaningful statistical analysis of most imaging parameters. Thus, only a descriptive analysis of the MRI data was possible. In 21/22 patients, MRI showeda decrease of the liver metastases. Best response was partial remission (PR) in 8/17 patients. Plasma concentrations of sVEGFR-2 and sVEGFR-3 decreased in all patients. The majority of the patients developed some kind of toxicity not always deducible to FOLFIRI or sunitinib. Conclusions Due to the observed side effect profile, FOLFIRI plus sunitinib 37.5 mg per day cannot be recommended for previously untreated mCRC.

Zielgerichtete Therapien spielen eine zunehmende Rolle in der medikamentosen Therapie von Tumorerkrankungen. Durch den gezielten Eingriff in molekulare Signalwege oder Immunreaktionen kommt es auch zu unerwunschten Wirkungen, die z. T. neuartig sind. Im Rahmen dieser Ubersichtsarbeit sollen die Nebenwirkungen von Multikinaseinhibitoren, Inhibitoren des MAP-Kinase-Signalwegs (EGFR-, KIT- und BRAF-Inhibitoren) sowie von CTLA-4-Inhibitoren besprochen werden. Recherche und Auswertung von Literatur. Die Kenntnis dieser Nebenwirkungen muss in klinischen Prufungen sorgfaltig erarbeitet werden und der behandelnde Arzt sollte umfassende Kenntnisse davon haben.

Background Peritoneal carcinomatosis (PC) is an unmet medical need. Despite recent improvements, systemic chemotherapy has limited efficacy. We report the first application of intraperitoneal chemotherapy as a pressurized aerosol in human patients. Methods Three end-stage patients with advanced PC from gastric, appendiceal, and ovarian origin were treated as a compassionate therapy. All patients had received previous systemic chemotherapy. A pressurized aerosol of CO2 loaded with doxorubicin 1.5 mg/m2 and cisplatin 7.5 mg/m2 (pressurized intraperitoneal aerosol chemotherapy, PIPAC) was applied into the abdomen for 30 min at a pressure of 12 mmHg and a temperature of 37 °C. Results No side-effects >2 CTCAE were observed, and the procedures were well tolerated. Early hospital discharge was possible (days 2–5). Nuclear presence of doxorubicin was documented throughout the peritoneum, reaching high local concentration (≤4.1 μmol/g) and plasma concentration was low (4.0–6.2 ng/ml). PIPAC created no significant adhesions, could be repeated, and was applied 6×, 4×, and 2×. Two patients showed a complete and one a partial histological remission. Mean survival after the first PIPAC was 288 days. One patient is alive after 567 days. Conclusions PIPAC shows superior pharmacological properties with high local concentration and low systemic exposure. PIPAC can induce regression of PC in chemoresistant tumors, using 10 % of a usual systemic dose. Electronic supplementary material The online version of this article (doi:10.1245/s10434-013-3213-1) contains supplementary material, which is available to authorized users.

Radioimmunotherapy is considered as treatment option in recurrent and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). To overcome the dose limiting bone marrow toxicity of IgG-based radioimmunoconjugates (RICs), we modified a humanized diabody with 5-, 10-, or 20-kDa polyethylene glycol (PEG) for CD22-targeted radioimmunotherapy using the low-energy β-emitter lutetium-177 ((177)Lu). A favorable pharmacokinetic profile was observed for the 10-kDa-PEG-diabody in nude mice being xenografted with subcutaneous human Burkitt lymphoma. Even at high doses of 16 MBq this diabody RIC was well tolerated by NOD Rag1(null) IL2rγ(null) (NRG) mice and did not reveal signs of organ long-term toxicity 80 days post injection. Combination therapy of the diabody RIC with unconjugated anti-CD20 Rituximab demonstrated therapeutic efficacy in established disseminated mantle cell lymphoma xenograft models. When compared with the combination of the IgG formatted (177)Lu anti-CD22 antibody and Rituximab, dual targeted therapy with the diabody RIC achieved an improved reduction of disease burden in the first nine days following treatment. The data indicate that the PEGylated anti-CD22 diabody may have potential for extending the repertoire of radiopharmaceuticals for the treatment of patients with B-NHL.

The aim of this work was to characterize the antitumoral activity of the plant compound 7-epi-nemorosone in prostate carcinoma cell lines. Prostate cancer is the most frequently diagnosed malignancy and the second-leading cause of cancer death in men. In spite of the current therapeutic options for this cancer entity, many patients die due to metastases in distant organs and acquired chemotherapy resistance. Thus, approaches to provide improvements in outcome and quality of life for such patients are urgently needed. Recently, the polyisoprenylated benzophenone 7-epi-nemorosone, originally collected by honeybees from Clusia rosea and Clusia grandiflora ( Clusiaceae ), has been described to be a potent antitumoral agent. Here, its activity in prostate carcinoma is reported. 7-epi-nemorosone was isolated from Caribbean propolis employing RP-HPLC techniques. Its cytotoxicity was assessed using the MTT proliferation assay in human androgen-dependent prostate carcinoma LNCaP cells including an MDR1 + sub-line. No cross-resistance was detected. FACS-based cell cycle analysis revealed a significant increase in the sub-G0/G1, G1, and depletion in the S phase populations. A concomitant down-regulation of cyclins D1/D3 and CDK 4/6 in LNCaP cells was detected by Western blot. Annexin-V-FITC labeling and caspase-3 cleavage assays showed that 7-epi-nemorosone induced apoptotic events. Major signal transduction elements such as p38 MAPK and Akt/PKB as well as androgen receptor AR and PSA production were found to be down-regulated after exposure to the drug. ERK1/2 protein levels and phosphorylation status were down-regulated accompanied by up-regulation but inhibition of the activity of their immediate upstream kinases MEK1/2. Additionally, Akt/PKB enzymatic activity was effectively inhibited at a similar concentration as for MEK1/2. Here, we demonstrate for the first time that 7-epi-nemorosone exerts cytotoxicity in an androgen-dependent prostate carcinoma entity by targeting the MEK1/2 signal transducer.

Background: BI 2536, a novel Polo-like kinase 1 inhibitor, was assessed in patients with unresectable advanced exocrine adenocarcinoma of the pancreas. Methods: The study employed a two-stage design. Randomised first-line patients received BI 2536 200 mg on day 1 (n=43) or 60 mg on days 1-3 (n=43) every 21 days. Recruitment of second-line patients was planned for a second stage dependent on an interim analysis demonstrating ≥2 responses in the first 18 evaluable patients following 12 weeks of treatment and/or tumour control ≥12 weeks in 5 patients per schedule. Primary end point was objective response rate (ORR). Results: By independent review, ORR was 2.3% (all partial) and 24.4% had stable disease as confirmed best response. The second stage was not initiated. Median overall and progression-free survivals were 149 (95% confidence interval (CI), 91-307) and 46 days (95% CI, 44-56). Most common drug-related adverse events were neutropenia (37.2%), leukopenia (29.1%), fatigue (29.1%) and nausea (22.1%); most common grade 3/4-related events were neutropenia (36.0%), leukopenia (27.9%) and thrombocytopenia (8.1%). Conclusion: Given the low ORR and poor survival, further development of BI 2536 monotherapy is not warranted in this population. © 2012 Cancer Research UK All rights reserved.

Sorafenib was the first oral antiangiogenic multikinase inhibitor (Raf kinases, VEGF receptors 1 - 3, PDGF-beta, Flt-3, c-kit) for advanced renal cell carcinoma (RCC) to be approved. Since 2005, a total of six drugs have been approved for the treatment of RCC.The preclinical and clinical development of sorafenib that led to its approval for advanced RCC is reviewed in this paper. Its safety, tolerability and efficacy are summarized and compared with other approved treatment options for RCC. Preliminary data on sequential treatment strategies and combination trials with other targeted drugs are also discussed.The efficacy and good tolerability of sorafenib in patients with RCC has already been confirmed by numerous studies. The drug proved to be suitable for patients of any age, with respect to efficacy and safety. Sequential use of sorafenib and other targeted drugs is characterized by only limited cross-resistance and many studies seem to indicate more clinical benefits and longer overall progression-free survival when sorafenib is administered as a first-line therapy. However, the optimal sequential therapy remains to be determined within prospective trials, such as the SWITCH study. In addition, we need predictive biomarkers to preselect the patients with the best chances of benefiting from sorafenib, in the context of personalized medicine.

Der vorliegende Beitrag beleuchtet endoskopische diagnostische und therapeutische Optionen in der Onkologie. Die Endosonographie ist ein Verfahren, das die Moglichkeiten der Endoskopie wesentlich bereichert, da es einen Blick uber die Oberflache der Mukosa hinaus in die umgebenden Strukturen und gezielte Interventionen ermoglicht. Es hielt Einzug in viele Leitlinien. Die Moglichkeiten und Grenzen der endoskopischen Behandlung von Fruhkarzinomen werden fur den Osophagus, den Magen und das Kolorektum aufgezeigt. Neue Materialien und Methoden bereichern die gastrointestinale Stenttherapie. Durch Stents oder mit den bereits gut etablierten perkutan-enteralen Sonden lassen sich in vielen kurativen und palliativen onkologischen Situationen masgeschneiderte Losungen finden.

Purpose S-1, an oral fluoropyrimidine derivative, has previously demonstrated anticancer efficacy in pancreatic cancer (PC), predominantly in Asian populations. This study evaluated the antitumor effect and safety of S-1 in Caucasian patients with metastatic PC. Methods Chemotherapy-naive patients received S-1 orally at 30 mg/m2 twice daily (BID) for 2 weeks, repeated every 3 weeks. Primary endpoint was ORR. Secondary endpoints included PFS, OS and safety assessment. The trial had a Simon’s two-stage design with 22 patients evaluable for efficacy in stage 1 and an additional 18 patients in stage 2, if ≥3/22 patients had a confirmed response at the first stage. Results Three out of 27 patients showed PR, however, detection of asymptomatic brain metastases in one of them prevented this study from proceeding to stage 2. The median PFS and OS for all patients was 3.5 and 9.1 months, respectively. The median duration of disease control for patients with SD or PR (n = 17) was 4.3 months. S-1 was well tolerated; fatigue was the most frequent grade 3/4 adverse event. Conclusions Efficacy data of PFS and OS are at least comparable to gemcitabine, the current standard of care. S-1 is active in Caucasian patients with metastatic PC.

Leukamien sind maligne Erkrankungen des blutbildenden Systems. Die Klassifikation basiert auf morphologischen, immunologischen und molekulargenetischen Eigenschaften der Leukamiezellen. Sowohl bei der akuten lymphatischen als auch bei der akuten myeloischen Leukamie wurden risikoadaptierte Behandlungen eingefuhrt, die zu Heilungsraten von ca. 40% bei jungeren Patienten fuhrten, mit allerdings grosen subgruppenspezifischen Unterschieden. Das Management der chronischen myeloischen Leukamie wurde durch molekular gezielte Therapien vollig geandert. Bei der chronischen lymphatischen Leukamie werden langer anhaltende Remissionen durch Purinanaloga und Antikorper erreicht. Die allogene Stammzelltransplantation hat die kurativen Therapieansatze erweitert. Die Strahlentherapie wird kurativ und palliativ eingesetzt. Der vorliegende Beitrag erlautert den aktuellen Stand der Diagnose und Therapie der einzelnen Leukamieformen im Erwachsenenalter.

Ein onkologischer Notfall tritt ein, wenn im Rahmen einer Tumorerkrankung direkt oder indirekt die Vitalparameter so weit beeintrachtigt werden, dass eine Lebensbedrohung entsteht. Eine Vielzahl von metabolischen Entgleisungen und Gerinnungsstorungen lassen sich direkt oder indirekt auf maligne Erkrankungen zuruckfuhren. Zu den typischen metabolisch bedingten onkologischen Notfallsituationen gehoren das Tumorlysesyndrom und akute Elektrolytverschiebungen wie Hyperkalzamie oder Hyponatriamie mit konsekutiven Organfunktionseinschrankungen. Sowohl Blutungs- als auch thromboembolische Ereignisse konnen Notfallsituationen bei onkologischen Patienten hervorrufen. Daruber hinaus ergeben sich durch das rasch wachsende Gebiet der Signaltransduktionsinhibitoren neue Nebenwirkungsprofile metabolischer Art (z. B. Hypophosphatamie, Hypothyreose), die der entsprechenden Erfahrung und vorbeugenden Masnahmen bedurfen, um bedrohliche Situationen rasch abwenden zu konnen.

There were only a few options 3 years ago to treat metastatic renal cell carcinoma (mRCC), a disease with a very poor prognosis. With the approval of targeted therapies for mRCC since December 2005, this situation has changed dramatically. Currently, oncologists can choose between several promising options to improve the longevity and quality of their patients' lives. A widely accepted treatment scheme for targeted therapies in mRCC does not yet exist. Based on a selective literature search, drawing on studies with six targeted therapies for mRCC, and including data from the latest American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) Annual Meetings, this review introduces the available therapies, evaluates patient-specific criteria for their application and suggests an algorithm for a patient-based treatment scheme. Clinical experiences with sequential therapies are summarized and potential combination therapies discussed. In conclusion, the crucial criteria of the treatment scheme we propose are the tumor burden and the disease pace, as well as the quality of life of a patient. These define whether tumor control or tumor remission should be the primary therapeutic goal. This scheme suggests which kind of therapeutic sequence to pursue to optimize patient care in mRCC.

Onkologische Notfalle sind relativ selten in der pathohistologischen Routinediagnostik. In den meisten Fallen handelt es sich um Erstmanifestationen maligner Tumoren, die eine rasche diagnostische Abklarung erfordern. Aufgabe der Pathologie ist in solchen Fallen die schnelle und valide Diagnostik potenziell kurabler Tumoren (z. B. Lymphome, Leukamien oder Keimzelltumoren). Prinzipiell sollte die Entscheidung zur Gewebeentnahme schnell erfolgen, am besten nach Absprache mit dem Pathologen. Der folgende Beitrag beschreibt ein rationelles diagnostisches Vorgehen anhand einiger Krankheitsbilder und diskutiert Moglichkeiten und Grenzen der Notfallpathologie.

Her2/neu protein overexpression and gene amplification is found in 20–30% of breast cancer patients and correlates with poor clinical outcome. Patients who profit from anti-Her2/neu- therapy are routinely selected by examination of tumour specimens using immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) separately. Many studies found a good correlation between both methods for score 1+ samples and for score 3+ samples, but not for score 2+ samples. In this study, we examined pleural and ascitic effusions with a combined approach using IHC and FISH on the same cells, under the following aspects: (1) frequency of Her2/neu protein expression and gene amplification in effusions; (2) correlation between score of protein expression and gene amplification; (3) impact of chromosome 17 polyploidy on Her2/neu protein expression. We examined 31 effusions from patients with breast cancer and 4 effusions from patients with ovarian cancer. Cytospins were analysed by IHC using two anti-Her2/neu antibodies and subsequently analysed by FISH with Her2/neu/CEP17 probes. Amplification was defined as: (1) Her2/neu gene copy number of more than 4 and (2) Her2/neu/CEP17 ratio of 2.0 or greater. A system combining IHC and FISH was developed and 35 effusion specimens were examined. As much as 25 of them were scored as positive. All of them contained cells with heterogeneous scores. A total of 18 of the samples contained cells with scores that ranged from 0 to 3+. In the other samples scores ranged from 0 to 1+ or 0 to 2+. Cells were analysed for Her2/neu gene amplification and chromosome 17 ploidy with regard to their scores. As much as 15 of all samples had mean Her2/neu copy numbers of >4, but only 12% (n = 3) of the positive samples were amplified according to Her2/neu/CEP17 ratio. Only 22, 9% (n = 8) were polyploid (mean CEP17 > 4); but 65, 7% (n = 23) of all specimens contained single polyploid cells. In some cases up to 100% of the score 3+ cells showed chromosome 17 polyploidy. Here protein overexpression might be caused by polyploidy rather than by gene amplification. In some samples, we found single cells with gene amplification but without protein expression and cells without amplification but with protein overexpression. The combination of IHC and FISH allows a differentiated analysis of single cells, which is especially important for effusions that are composed of heterogeneous cells. Therefore, cells with high gene amplification and/or protein overexpression can be detected and analysed even if their amount in the sample is small. Chromosome 17 polyploidy is important in some cases but this should be further examined on a larger series.

Telatinib (BAY 57-9352) is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptors 2 and 3 (VEGFR-2/-3) and platelet-derived growth factor receptor beta tyrosine kinases. In this multicentre phase I dose escalation study, 71 patients with refractory solid tumours were enroled into 14 days on/7 days off (noncontinuous dosing) or continuous dosing groups to receive telatinib two times daily (BID). Hypertension (23%) and diarrhoea (7%) were the most frequent study drug-related adverse events of CTC grade 3. The maximum-tolerated dose was not reached up to a dose of 1500 mg BID continuous dosing. Telatinib was rapidly absorbed with median t(max) of 3 hours or less. Geometric mean C(max) and AUC(0-12) increased in a less than dose-proportional manner and plateaued in the 900-1500 mg BID dose range. Two renal cell carcinoma patients reached a partial response. Tumour blood flow measured by contrast-enhanced magnetic resonance imaging and sVEGFR-2 plasma levels decreased with increasing AUC(0-12) of telatinib. Telatinib is safe and well tolerated up to a dose of 1500 mg BID continuous dosing. Based on pharmacokinetic and pharmacodynamic criteria, 900 mg telatinib BID continuously administered was selected as the recommended phase II dose.

In this study, we investigated the kinetics of oxaliplatin-DNA adduct formation in white blood cells of cancer patients in relation to efficacy as well as oxaliplatin-associated neurotoxicity. Thirty-seven patients with various solid tumours received 130 mg m(-2) oxaliplatin as a 2-h infusion. Oxaliplatin-DNA adduct levels were measured in the first cycle using adsorptive stripping voltammetry. Platinum concentrations were measured in ultrafiltrate and plasma using a validated flameless atomic absorption spectrometry method. DNA adduct levels showed a characteristic time course, but were not correlated to platinum pharmacokinetics and varied considerably among individuals. In patients showing tumour response, adduct levels after 24 and 48 h were significantly higher than in nonresponders. Oxaliplatin-induced neurotoxicity was more pronounced but was not significantly different in patients with high adduct levels. The potential of oxaliplatin-DNA adduct measurements as pharmacodynamic end point should be further investigated in future trials.

Vor der Therapie des Osophaguskarzinoms muss zwischen Plattenepithel- und Adenokarzinom unterschieden werden, auch wenn die R0-Resektion als entscheidendes Therapieziel fur beide Tumorentitaten gilt. Inzwischen lasst sich das Stadium praoperativ sehr gut erfassen. Eine Risikoanalyse kann bei den aufwandigen Zweihohleneingriffen zu einer adaquaten Patientenselektion beitragen. Unter den multimodalen Protokollen haben sich vor allem die neoadjuvante Radio-Chemo-Therapie fur das Plattenepithelkarzinom und die neoadjuvante Chemotherapie fur das Adenokarzinom des distalen Osophagus bewahrt. Bei Letzteren ist es moglich, mittels PET ein fruhzeitiges Therapieansprechen zu detektieren. Auch die chirurgische Therapie ist standardisiert, die subtotale Osophagektomie mit intrathorakaler Anastomose ist das Verfahren der Wahl. Ein modernes Komplikationsmanagement hat Morbiditat und Letalitat der Resektion signifikant gesenkt. Nach Ansprechen auf die Vorbehandlung und nach kompletter Resektion ist die Prognose der Patienten inzwischen deutlich verbessert worden. Damit sind auch aggressive Therapieoptionen durchfuhrbar mit nachgewiesener Prognoseverbesserung fur viele Patienten.

Sorafenib is a multi-kinase inhibitor with antiangiogenic and antiproliferative activity. The activity of sorafenib in progressive hormone-refractory prostate cancer (HRPC) patients was investigated in a phase II clinical study. Progressive HRPC patients received sorafenib 400 mg bid p.o. continuously. Only patients with no prior chemotherapy, and either one-unidimensional measurable lesion according to RECIST-criteria or increasing prostate-specific antigen (PSA) values reflecting a hormone-refractory situation, were eligible for study entry. The primary study objective was the rate of progression-free survival of ⩾12 weeks (PFS12). Secondary end points were overall response, overall survival, and toxicity. Fifty-seven patients with PC were enrolled. Two patients had to be withdrawn from the set of eligible patients. According to RECIST criteria, 4 patients out of 55 evaluable patients showed stable disease (SD). According to PSA–response, we saw 11 patients with SD PSA and 2 patients were responders at 12 weeks (PFS12=17/55=31%). Among the 257 adverse events, 15 were considered drug related of maximum CTC-grade 3. Twenty-four serious adverse events occurred in 14 patients (14/55=26%). Seven of them were determined to be drug related. No treatment-related death was observed. Sorafenib has antitumour activity in HRPCP when evaluated for RECIST- and PSA-based response. Further investigation as a component of combination regimens is necessary to evaluate its definite or overall clinical benefit for HRPCP.

BACKGROUND. S-1 is a promising oral fluoropyrimidine. The authors obtained extended Phase II safety and efficacy data in a multicenter setting for the S-1 plus cisplatin combination: The experimental arm of the global Phase III First-Line Advanced Gastric Cancer Study (FLAGS) is being compared with 5-fluorouracil/cisplatin. METHODS. Eligible patients had untreated, histologically confirmed advanced gastric cancer (AGC), a Karnofsky performance status (KPS) ≥70%, adequate organ function, and provided written consent. Patients received S-1 (25 mg/m2 twice daily on Days 1 through 21) plus cisplatin (75 mg/m2 on Day 1) every 28 days. The confirmed overall response rate (CORR) also was designated by an external review. The time to progression (TTP), median survival (MS), and safety were assessed. RESULTS. All 72 patients were assessed for safety and survival, and 64 patients were assessed for CORR. The median KPS was 90%. The median number of treatment cycles was 4. The CORR was 55% (95% confidence interval [95% CI], 42–67%). The median duration of response was >5 months. At 6 months, only an estimated 38% of patients had cancer progression. The estimated MS was 10.4 months (95% CI, 8.6–12.9 months). At least 1 serious adverse event occurred in 44% of patients. The frequent grade 3 or 4 toxicities (using the National Cancer Institute Common Toxicity Criteria), which occurred in >10% of patients, included fatigue/asthenia (24%), emesis (17%), nausea (15%), diarrhea (13%), and neutropenia (19%). Complicated neutropenia (1.4%) and grade 4 diarrhea (1.4%) were rare. CONCLUSIONS. The current extended data confirmed that S-1 combined with cisplatin had a highly desirable safety profile. The efficacy against AGC, according to an external review, was encouraging. FLAGS is expected to complete its accrual of 1050 patients by December 2007. Cancer 2007. © 2006 American Cancer Society.

Background The oral multikinase inhibitor regorafenib improves overall survival (OS) in patients with metastatic colorectal cancer (CRC) for which all standard treatments have failed. This study investigated regorafenib plus modified FOLFOX (mFOLFOX6) as first-line treatment of metastatic CRC. Methods In this single-arm, open-label, multicentre, phase II study, patients received mFOLFOX6 on days 1 and 15, and regorafenib 160 mg orally once daily on days 4-10 and 18-24 of each 28-day cycle. The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included disease control rate (DCR), OS, progression-free survival (PFS) and safety. Results Median overall treatment duration with any study drug was 9.9 months (range 0.6-19.6); median treatment duration with regorafenib was 7.7 months (range 0.1-19.5); six patients remained on regorafenib for more than 1 year. Fifty-three patients received at least one dose of regorafenib. ORR was 43.9% (all partial responses); DCR was 85.4%; median OS was not reached; median PFS was 8.5 months. Treatment-emergent adverse events were experienced by all patients but were manageable with dose modifications. Conclusion Regorafenib + mFOLFOX6 as first-line treatment in patients with metastatic CRC did not improve ORR over historical controls. Regorafenib plus mFOLFOX6 did not appear to be associated with a markedly worse tolerability profile versus mFOLFOX6 alone. ClinicalTrials.gov identifier: NCT01289821.