Evaluation of the inflammation-based modified Glasgow Prognostic Score (mGPS) as a prognostic and predictive biomarker in patients with metastatic colorectal cancer receiving first-line chemotherapy: a post hoc analysis of the randomized phase III XELAVIRI trial (AIO KRK0110).

BACKGROUND: The inflammation-based modified Glasgow Prognostic Score (mGPS) combines serum levels of C-reactive protein and albumin and was shown to predict survival in advanced cancer. We aimed to elucidate the prognostic impact of mGPS on survival as well as its predictive value when combined with gender in unselected metastatic colorectal cancer (mCRC) patients receiving first-line chemotherapy in the randomized phase III XELAVIRI trial. PATIENTS AND METHODS: In XELAVIRI, mCRC patients were treated with either fluoropyrimidine/bevacizumab followed by additional irinotecan at first progression (sequential treatment arm; Arm A) or upfront combination of fluoropyrimidine/bevacizumab/irinotecan (intensive treatment arm; Arm B). In the present post hoc analysis, survival was evaluated with respect to the assorted mGPS categories 0, 1 or 2. Interaction between mGPS and gender was analyzed. RESULTS: Out of 421 mCRC patients treated in XELAVIRI, 362 [119 women (32.9%) and 243 men (67.1%)] were assessable. For the entire study population a significant association between mGPS and overall survival (OS) was observed [mGPS = 0: median 28.9 months, 95% confidence interval (CI) 25.9-33.6 months; mGPS = 1: median 21.4 months, 95% CI 17.6-26.1 months; mGPS = 2: median 16.8 months, 95% CI 14.3-21.2 months; P < 0.00001]. Similar results were found when comparing progression-free survival between groups. The effect of mGPS on survival did not depend on the applied treatment regimen (P = 0.21). In female patients, a trend towards longer OS was observed in Arm A versus Arm B, with this effect being clearly more pronounced in the mGPS cohort 0 (41.6 versus 25.5 months; P = 0.056). By contrast, median OS was longer in male patients with an mGPS of 1-2 treated in Arm B versus Arm A (20.8 versus 17.4 months; P = 0.022). CONCLUSION: We demonstrate the role of mGPS as an independent predictor of OS regardless of the treatment regimen in mCRC patients receiving first-line treatment. mGPS may help identify gender-specific subgroups that benefit more or less from upfront intensive therapy.

CONKO-006: A randomised double-blinded phase IIb-study of additive therapy with gemcitabine + sorafenib/placebo in patients with R1 resection of pancreatic cancer - Final results.

BACKGROUND: CONKO-006 was designed for patients with pancreatic adenocarcinoma with postsurgical R1 residual status to evaluate the efficacy and safety of the combination of gemcitabine and sorafenib (GemSorafenib) compared with those of gemcitabine + placebo (GemP) for 12 cycles. PATIENTS AND METHODS: This randomised, double-blind, placebo-controlled, multicenter study was planned to detect an improvement in recurrence-free survival (RFS) from 42% to 60% after 18 months. Secondary objectives were overall survival (OS), safety and duration of treatment. RESULTS: 122 patients were included between 02/2008 and 09/2013; 57 were randomised to GemSorafenib and 65 to GemP. Patient characteristics were wellbalanced (GemSorafenib/GemP) in terms of median age (63/63 years), tumour size (T3/T4: 97/97%), and nodal positivity (86/85%). Grade 3/4 toxicities comprised diarrhoea (GemSorafenib: 12%; GemP: 2%), elevated gamma-glutamyl transferase (GGT) (19%; 9%), fatigue (5%; 2%) and hypertension (5%; 2%), as well as neutropenia (18%; 25%) and thrombocytopenia (9%; 2%). By August 2017, 118 (97%) RFS event had occurred. There were no difference in RFS (median GemSorafenib: 8.5 versus GemP: 9.4 months; p = 0.730) nor OS (median GemSorafenib: 17.6 versus GemP: 17.5 months; p = 0.481). Landmark analyses suggest that patients who received more than six cycles of postoperative chemotherapy had significantly longer OS (p = 0.021). CONCLUSION: CONKO-006 is the first randomised clinical trial to include exclusively patients with PDAC with postsurgical R1 status thus far. Sorafenib added to gemcitabine did neither improve RFS nor OS. However, postoperative treatment exceeding six months seemed to prolong survival and should be further investigated in these high-risk patients. CLINICAL TRIAL INFORMATION: German Tumor Study Registry (Deutsches Krebsstudienregister), DRKS00000242.

Long-term treatment of advanced hepatocellular carcinoma with the tyrosine kinase inhibitor erlotinib (Tarceva)--a case report.

AIM: Hepatocellular carcinoma (HCC) is the 5th most common human malignancy with an increasing incidence in western countries and still unsatisfactory median survival rates of 5 - 7 months. Currently, new treatments with biologicals (so-called "targed therapies") such as VEGF and EGF antibodies or tyrosine kinase inhibitors (e. g., sorafenib) are being tested in patients with HCC. Here we report a long-term treatment of an advanced, multifocal HCC with the tyrosine kinase inhibitor erlotinib (Tarceva). PATIENT AND METHODS: A 64-year-old man with newly diagnosed and histologically proven advanced HCC and hydropic liver cirrhosis (Child-Pugh B) was treated for 18 months (12 / 05 - 06 / 07) with erlotinib. In addition paracentesis was performed every 6 weeks to provide relief from ascites. RESULTS: After 2 weeks of treatment with 100 mg erlotinib QD the patient developed a 3 degrees-4 degrees skin toxicity (haemorrhagic rush). Other major side effects did not occur. Erlotinib medication was stopped for 2 weeks and re-started at a reduced dose of 75 mg QD. Marker tumour lesions (No. 1: caudate lobe/No. 2: segment III), liver enzymes and synthesis parameters (albumin, prothrombin time/INR) and frequency of paracentesis remained stable during the 18 months of observation. CONCLUSIONS: Erlotinib (Tarceva) appears to be an interesting treatment option for patients with advanced HCC. More clinical data and studies are needed to confirm this result.

Gemtuzumab ozogamicin (Mylotarg) as single-agent treatment for frail patients 61 years of age and older with acute myeloid leukemia: final results of AML-15B, a phase 2 study of the European Organisation for Research and Treatment of Cancer and Gruppo Italiano Malattie Ematologiche dell'Adulto Leukemia Groups.

The therapeutic activity and toxicity profile of gemtuzumab ozogamicin were assessed in 40 patients >60 years of age with acute myeloid leukemia (AML) who were not considered eligible for conventional chemotherapy because of advanced age or poor performance status. The drug was administered at the dose of 9 mg/m2 as a single 2-h i.v. infusion on days 1 and 15. Patients who achieved a complete remission (CR/CRp) were to receive a consolidation with two additional injections of the immunotoxin at the same dose. The overall CR/CRp rate was 17% (95% CI, 8-32%). The CR/CRp rate in patients 61-75 years old was 33% (6/18), and 5% (1/22) in patients older than 75 years. Induction death occurred in seven patients (17%), all aged above 75 years. Overall survival was significantly longer in patients aged 61-75 years than in older individuals (P=0.05), and in CD33+ cases than in CD33- cases (P=0.05). We conclude that the dose/schedule of gemtuzumab ozogamicin used in this trial is too toxic in the age group over 75 years. For these patients, additional studies with reduced doses of the immunotoxin are warranted.

Takayasu's arteritis secondary to myelodysplasia as a predictor of poor outcome: two case reports.

We present two patients with myelodysplasia in association with Takayasu's arteritis (TA). In both patients intensive immunosuppressive treatment could not control the vascular inflammation. Subsequently both patients developed myelodysplasia, rapidly progressing to secondary acute myelogenous leukaemia. One patient had a peripheral blood stem cell transplant from a compatible sibling donor, but died of refractory leukaemia 5 months later. The other patient died of fungal sepsis. These are the first two patients reported to have TA associated with myelodysplasia/secondary leukaemia.

Complete remission of third recurrence of acute myeloid leukemia after treatment with imatinib (STI-571).

We report the case of a 76-year old patient with third relapse of AML who was successfully treated with Imatinib. The decision to try Imatinib was guided by bright expression of c-kit on the patient's blasts. Treatment was well tolerated but the dose was reduced for pancytopenia and later stopped completely because of pneumonia. The patient recovered with i.v. antibiotics, antimycotics and s.c. G-CSF. Reevaluation of the bone marrow after the end of treatment demonstrated the absence of malignant blasts. Treatment with Imatinib was started again with the intention to prolong remission duration. During the following months peripheral blood counts stabilized in the normal range indicating that a fourth complete remission has been achieved in this patient. This is the first report demonstrating that Imatinib can induce complete remission in relapsed c-kit positive AML in an elderly patient. Prolonged cytopenia remains a considerable problem indicating that normal haematopoiesis is not completely independent of the signalling cascades inhibited by Imatinib. Nevertheless our report supports further study of this drug in c-kit positive AML.

[Multimodal treatment strategy for Langerhans cell histiocytosis at head and neck manifestations]. / Interdisziplinäre Therapie der Langerhans-Zell-Histiozytose im Kopf- und Halsbereich.

Langerhans cell histiocytosis (LCH) is a rare disorder with different clinical features. An established standardized treatment does not exist.We present a case report of a patient with localized LCH of the temporal bone and discuss the interdisciplinary treatment strategies. We reviewed the international literature and summarized the current knowledge. Beside a wait and see policy in cases without symptomatic disease, surgery, radiotherapy or chemotherapy, and combinations of these options are used as treatment modalities. While surgery or radiotherapy are preferred in localized (symptomatic) lesions, stage-adapted chemotherapeutic regimens are the treatments of choice in disseminated disease. Treatment selection depends on the individual clinical features.

Potentially therapeutically relevant differences of antisense oligonucleotide uptake in CD34+ hematopoietic stem cells, leukemic blasts and cancer cells from patients.

Antisense oligonucleotide (ON) technology, e.g. against drug resistance or antiapoptotic factors, may play an important role in future cancer chemotherapy. An unanswered question in this field is the capacity for uptake of antisense molecules in normal and malignant patients' cells. Therefore, we examined the cellular uptake of FITC-labeled phosphorothioate modified ONs in: i) cells from the T-lymphoblastoid cell line CCRF-CEM, ii) CD34+ hematopoietic progenitors from healthy donors, iii) blasts from ALL or AML patients, iv) cells from the ovarian cancer cell line A2780 and v) cancer cells from malignant fluids. The cationic polymer ExGen was taken as a carrier for transfection, while FITC-ON uptake was evaluated by flow cytometry. We found marked differences between these cell types. Cancer cells from the cell line A2780 and from patients showed a distinctly enhanced uptake compared to hematopoietic progenitors and leukemic blasts. Since bone marrow toxicity substantially limits any conventional chemotherapeutic regimen, a better ON uptake in cancer cells compared to hematopoietic precursors might give an advantage for therapeutic approaches using e.g. ON-based chemosensitization.

Transendothelial migration of hematopoietic progenitor cells. Role of chemotactic factors.

There is increasing evidence that hematopoietic stem cell mobilization and homing is regulated not only by adhesion molecules and cytokines, but also by chemotactic factors that support transendothelial migration across the bone marrow sinusoidal endothelium. Many receptors for chemotactic mediators belong to the family of G protein-coupled seven-transmembrane receptors (7-TMR). Signaling via G proteins, particularly Gi proteins, results in a chemotactic response of the cells towards a gradient of the corresponding ligand. Recent studies have provided evidence for expression of several 7-TMR on immature hematopoietic progenitor cells, which potentially mediate chemotactic effects: chemokine receptors (e.g., CXCR4, receptor for stromal cell-derived factor-1), receptors for lipid mediators (e.g., the cysteinyl leukotriene receptor cysLT1 and the peripheral cannabinoid receptor cb2), and receptors for neuroendocrine hormones (e.g., the somatostatin receptor sst2). From these studies it can be concluded that migration of hematopoietic progenitor and stem cells is controlled by a variety of chemotactic factors rather than by a single chemokine (e.g., SDF-1). Trafficking of immature hematopoietic cells may require combined and interactive regulatory functions of these mediators.

High-grade lymphoma mimicking bone crisis in Gaucher's disease.

A 33-year-old woman with type 1 Gaucher's disease developed painful swelling of her right tibia. Initial diagnostics suggested a typical bone crisis. However, clinical course and subsequent imaging pointed to malignant disease, which was specified as high-grade lymphoma. Chemotherapy was applied together with enzyme replacement and resulted in complete remission of the lymphoma. We conclude that osseous lesions, although suggestive of common manifestations of Gaucher's disease, should be discriminated very carefully from neoplastic infiltration to maintain curative treatment options.

Chemotaxis and transendothelial migration of CD34(+) hematopoietic progenitor cells induced by the inflammatory mediator leukotriene D4 are mediated by the 7-transmembrane receptor CysLT1.

Recent studies suggest that bone marrow (BM)-derived chemotactic mediators such as chemokines play key roles in hematopoietic stem cell trafficking. Lipid mediators, particularly leukotrienes, are involved in leukocyte chemotaxis during inflammation but have also been detected in the normal BM. Therefore, the effects of leukotrienes on hematopoietic progenitor cells were analyzed. Cysteinyl leukotrienes, particularly leukotriene D4 (LTD4), induced strong intracellular calcium fluxes and actin polymerization in mobilized and BM CD34(+) progenitors. Chemotaxis and in vitro transendothelial migration of CD34(+) and more primitive CD34(+)/CD38(-) cells were 2-fold increased by LTD4 at an optimum concentration of 25 to 50 nM. Accordingly, CD34(+) cells expressed the 7-transmembrane LTD4 receptor CysLT1 by reverse transcriptase-polymerase chain reaction and Western blot. Effects of LTD4 were suppressed by the CysLT1 receptor antagonist MK-571 and reduced by pertussis toxin. In contrast, LTB4 induced strong responses only in mature granulocytes. LTD4-induced calcium fluxes were also observed in granulocytes but were not reduced by MK-571, suggesting that these effects were mediated by other receptors (eg, CysLT2) rather than by CysLT1. In addition, expression of 5-lipoxygenase, the key enzyme of leukotriene biosynthesis, was detected in both hematopoietic progenitor cells and mature leukocytes. The study concludes that the functionally active LTD4 receptor CysLT1 is preferentially expressed in immature hematopoietic progenitor cells. LTD4 released in the BM might regulate progenitor cell trafficking and could also act as an autocrine mediator of hematopoiesis. This would be a first physiologic effect of cysteinyl leukotrienes apart from the many known pathophysiologic actions related to allergy and inflammation. (Blood. 2001;97:3433-3440)

Low-dose melphalan induces favourable responses in elderly patients with high-risk myelodysplastic syndromes or secondary acute myeloid leukaemia.

We treated 21 elderly patients with high-risk myelodysplasia (n = 14) or secondary acute myeloid leukaemia (n = 7) with 2 mg of melphalan orally once a day until a complete peripheral response was obtained or until there was evidence of treatment failure. We observed seven (30%) complete and two (10%) partial peripheral responses occurring within 4-16 weeks and lasting for 12 + to 55 weeks. In relapse, retreatment was successful in most of the patients. Responses were associated with the absence of complex cytogenetic abnormalities and with a normal or reduced bone marrow cellularity.

Functional analysis of P-glycoprotein and multidrug resistance associated protein related multidrug resistance in AML-blasts.

Despite the high effectiveness of various P-glycoprotein (P-gp) modulating substances in vitro their clinical value e.g. for combination treatment of acute myelogenous leukemias (AML) remains still unclear. This might be explainable by recent findings that other factors than P-gp (e.g. the multidrug resistance associated protein (MRP)) may also be involved in clinical occurring drug resistance. To study P-gp and MRP mediated MDR in AML blasts from patients with relapses at the functional level we measured rhodamine 123 (RHO) efflux in combination with a P-gp specific (SDZ PSC 833) or a MRP specific (MK571) modulator, respectively. Furthermore, direct antineoplastic drug action was monitored by determination of damaged cell fraction of a blast population using flow cytometry. We generally found strongly modulated RHO efflux by SDZ PSC 833 but slight RHO-efflux modulation by MK571 in blasts from relapsed states of AML expressing MDR1 or MRP mRNA at various levels. We could not demonstrate, though, significant PSC 833 or MK571 mediated modulation of the cytotoxic effects of etoposide. The results point to the possibility that combination of etoposide and a modulator might not improve responses to chemotherapy by targeting P-gp or MRP exclusively.

Human parvovirus B19-associated disease in bone marrow transplantation.

Human parvovirus B19 can persist in immunocompromised patients and may produce severe clinical illness. In this retrospective study the incidence of B19-associated infections in bone marrow transplant patients was investigated. During 1 year 60 patients received bone marrow grafts (eight autografts and 52 allogeneic transplantations). In case of early onset, atypical or steroid-resistant erythrodermia the patients' blood and/or tissue specimens were screened for B19 infection by polymerase chain reaction (PCR). Additionally, specimens of patients with severe organ failure were tested. A total of 64 PCRs was performed in 27 patients. Seven patients with erythrodermia and one with vulvovaginitis proved to be PCR positive. In patients with organ failure B19 DNA was detected in the myocardium and liver. The incidence of B19 infections in this cohort was 15% and the B19-associated mortality rate 7%. In conclusion, parvovirus B19-associated infections may be more common in immunocompromised patients than previously anticipated.

Release of prostaglandin D2 by murine mast cells: importance of metabolite formation for antiproliferative activity.

Prostaglandin (PG) D2, PGJ2 and delta12-PGJ2 are antiproliferative eicosanoids. We investigated the production of PGD2 by murine bone marrow-derived mast cells (BMMC) taking into consideration metabolism of PGD2 to PGD2 and delta12-PGJ2. PG-metabolites were quantified by high performance liquid chromatography (HPLC) combined with radioimmunoassay (RIA). Stimulated with calcium ionophore A23187 BMMC released eight-fold more PGJ2 and delta12-PGJ2 than PGD2. Conversion of endogenously produced PGD2 to PGJ2 and delta12-PGJ2 proceeded rapidly in contrast to metabolism of exogenously added PGD2. The antiproliferative potency of these prostaglandins is demonstrated in vitro. We conclude that determination of PGD2 production by mast cells must take into consideration rapid conversion to active derivatives, which may play a significant role in growth regulation.

Poor response rate to a continuous schedule of Amifostine therapy for 'low/intermediate risk' myelodysplastic patients.

Ineffective haemopoiesis leading to cytopenia presents the major clinical management problem for patients with myelodysplasia (MDS). Preliminary studies have demonstrated that the synthetic aminothiol Amifostine stimulates multilineage haemopoiesis both in vitro and in vivo in patients with MDS. We have treated 12 patients with an uninterrupted 8-week schedule of thrice-weekly intravenous Amifostine with a starting dose of 300 mg/m2 escalating to 450 mg/m2 in non-responders. No patients satisfied response criteria on study but two patients showed minor responses. We conclude that therapeutic response to Amifostine in MDS may be schedule dependent.

Sulfite induces release of lipid mediators by alveolar macrophages.

Air pollutants are supposed to modulate physiological responses of alveolar macrophages (AM). This study was addressed to the question whether at neutral pH sulfur(IV) species in comparison to sulfur(VI) species cause AM to release proinflammatory mediators and which pathways are involved in their generation. Supernatants obtained from canine AM treated with sulfite (0.1 mM to 2 mM) enhanced the respiratory burst of canine neutrophils, measured by lucigenin-dependent chemiluminescence, whereas supernatants derived from AM treated with sulfite (1 mM) did not. The neutrophil-stimulating activity released by sulfite-treated AM consisted of platelet-activating factor (PAF) and leukotriene B4 (LTB4) as shown by desensitization of the corresponding receptors. Inhibitors of phospholipase A2 substantially suppressed release of neutrophil-stimulating activity by sulfite-treated AM. Inhibition of 5-lipoxygenase in sulfite-treated AM also reduced neutrophil-stimulating activity, while inhibition of cyclooxygenase had no effect. In conclusion, sulfite induces AM to release lipid mediators via phospholipase A2- and 5-lipoxygenase-dependent pathways. These mediators activate neutrophils via the receptors for PAF and LTB4.

MK-886, a leukotriene biosynthesis inhibitor, induces antiproliferative effects and apoptosis in HL-60 cells.

MK-886, a specific inhibitor of 5-lipoxygenase inhibited DNA replication in leukemic HL-60 cells in a dose-dependent manner. Addition of exogenous leukotriene B4 reversed this effect, whereas addition of leukotriene B4 failed to modulate a prostaglandin D2-induced inhibition of DNA replication. The reversal of MK-886-induced inhibition was not observed with leukotriene C4. These results suggest that the effect of MK-886 is mediated by inhibition of leukotriene B4 biosynthesis. Moreover, MK-886 not only impaired DNA replication in HL-60 cells but also decreased cell proliferation and induced apoptotic cell death. Our results suggest a crucial role of leukotriene B4 in the regulation of cell proliferation and cell survival in HL-60 cells.