Communicative reprogramming non-curative hepatocellular carcinoma with low-dose metronomic chemotherapy, COX-2 inhibitor and PPAR-gamma agonist: a phase II trial.

Systemic therapy for advanced hepatocellular carcinoma (HCC) is still challenging. A biomodulatory therapy approach targeting the communicative infrastructure of HCC, including metronomic low-dose chemotherapy with capecitabine, pioglitazone and rofecoxib, has been evaluated in patients with non-curative HCC. Altogether 38 patients were evaluable in this one-arm, multicenter phase II trial. The primary endpoint, median progression-free survival was 2.7 months (95% CI: 1.6-3.79) for all evaluable patients and 8.4 months (95% CI: 0-18.13) for patients ≥ 6 weeks on protocol. Median overall survival (OS) was 6.7 months (95% CI: 4.08-9.31) and 9.4 months (95% CI: 4.82-13.97), respectively. Most common adverse events were edemas grade 3, which were commonly related to the advanced stage, with 66% of the patients suffering from liver cirrhosis. Exploratory data analyses showed significant impact of ECOG performance status grade 0 versus 1 and CLIP score 0/1 versus > 1 on OS, 9.8 months (95% CI: 4.24-15.35) versus 2.7 months (95% CI: 1.03-4.36; P = 0.002), and 9.8 months (95% CI: 3.23-16.37) versus 4.4 months (95% CI: 3.14-5.66; P = 0.009), respectively. Preceding tumor surgery had significant beneficial impact on survival, as well as maximal tumor diameter of < 5 cm. The correlation of C-reactive protein decrease with significantly improved OS underlines the close link between inflammation and tumor control. Biomodulatory therapy in advanced HCC may be a low toxic, efficacious treatment and principally demonstrates that such approaches should be followed further for treatment of advanced HCC.

Biomodulatory Treatment of Patients with Castration-Resistant Prostate Cancer: A Phase II Study of Imatinib with Pioglitazone, Etoricoxib, Dexamethasone and Low-Dose Treosulfan.

Therapeutic options for patients with castration-resistant prostate cancer (CRPC) remain limited. In a multicenter, Phase II study, 65 patients with histologically confirmed CRPC received a biomodulatory regimen during the six-month core study. Treatment comprised daily doses of imatinib mesylate, pioglitazone, etoricoxib, treosulfan and dexamethasone. The primary endpoint was prostate-specific antigen (PSA) response. Responders could enter an extension phase until disease progression or intolerable toxicity occurred. Mean PSA was 45.3 ng/mL at baseline, and 77 % of patients had a PSA doubling time <3 months. Of the 61 evaluable patients, 37 patients (60.6 %) responded or had stable disease and 23 of them (37.7 % of 61 patients) were PSA responders. Among the 23 responders mean PSA decreased from 278.9 ± 784.1 ng/mL at baseline to 8.8 ± 11.6 ng/mL at the final visit (week 24). The progression-free survival (PFS) was 467 days in the ITT population. Of the 947 adverse events, 57.6 % were suspected to be drug-related, 13.8 % led to dose adjustment or permanent discontinuation and 40.2 % required concomitant medication. This novel combination approach led to an impressive PSA response rate of 37.7 % in CRPC patients. The good PSA response and PFS rate combined with the manageable toxicity profile suggest an alternative treatment option.

Extracorporeal photopheresis in 62 patients with acute and chronic GVHD: results of treatment with the COBE Spectra System.

In this retrospective analysis, 30 patients with acute GVHD (aGVHD) and 32 patients with chronic GVHD (cGVHD) treated with extracorporeal photopheresis (ECP) performed by the COBE Spectra System were evaluated. After 3 months of ECP treatment, a CR and PR were observed in 9 (30%) and 6 (20%) patients with aGVHD and in 2 (6%) and 12 (38%) patients with cGVHD. In 16 (53%) patients with aGVHD and 9 (28%) with cGVHD ECP treatment was already stopped after 3 months. One (3%) patient with aGVHD and 7 (22%) patients with cGVHD received new additional immunosuppressive therapy started during the first 3 months of ECP treatment and were classified as 'nonresponder' with regard to ECP. Of these patients a PR was achieved in one patient with aGVHD and in three patients with cGVHD. Steroids could be tapered by 50 in 83% of patients with aGVHD and in 29% of patients with cGVHD after 3 months of ECP treatment. Patients with aGVHD achieving a CR or PR showed a significant improved OS after allo-SCT (P=0.019). ECP is associated with significant response rates and successful reduction of steroids in patients with GVHD.

[Unusual skin alterations in a 72-year-old patient with multiple myeloma]. / Ungewöhnliche Hautveränderungen bei 72-jähriger Patientin mit multiplem Myelom.

We report on a 72-year-old female patient with multiple myeloma who presented with alopecia and eye-catching alterations of the skin and the nails. A biopsy of the skin could confirm the diagnosis of immunoglobulin light chain (AL) amyloidosis, which was also suspected of having affected other organs. After six cycles of a cytoreductive therapy with bortezomib and dexamethasone a very good partial response of the multiple myeloma was seen and an improvement in the skin and nail alterations could be achieved.

Pioglitazone, etoricoxib, interferon-α, and metronomic capecitabine for metastatic renal cell carcinoma: final results of a prospective phase II trial.

We enrolled 45 patients with metastatic renal cell carcinoma (RCC) at a progressive disease between March 2003 and April 2008 to assess the impact of an anti-inflammatory treatment regime in combination with metronomic low-dose chemotherapy. 42% of the patients had been systemically pre-treated. Therapy consisted of etoricoxib 60 mg daily plus pioglitazone 60 mg daily, day 1+, low-dose interferon-α 4.5 MU sc three times a week, week 1+ and low-dose capecitabine 1 g/m(2) twice daily orally for 14 days, every 3 weeks, day 1+, until disease progression. Objective response was observed in 35% of the patients (PR 27, CR 9%), which was paralleled by strong CRP decline for all patients with initially elevated CRP levels (n = 32). CRP values decreased from mean 42.3 mg/L (range 9.1-236), to 11.1 mg/L, (range 1.1-35.6), P = 0.006. Median overall survival and progression-free survival for the total cohort were 26.9 and 7.2 months for patients with elevated CRP 24.4 and 11.3 months (95% CI, 22.8-31.0/5.7-16.9) and 13.8-2.6 months (95% CI, 6.5-21.1/0.4-4.8) for the non-elevated CRP group, respectively (P = 0.082/0.017). Median observation time: 26.1 months; Overall survival at 5 years: 18%. Toxicity>WHO grade 3 was reported: Hand-foot syndrome in 16 patients (36%), diarrhea in 4, and pneumonia in 2 patients. Our data allow us to conclude that the control of tumor-associated inflammation is an important therapeutic principle in patients with metastatic RCC.

Vaccination against pandemic H1N1 (2009) in patients after allogeneic hematopoietic stem cell transplantation: a retrospective analysis.

PURPOSE: Limited data are available on immunologic responses to primary pandemic H1N1 (2009) vaccination in recipients of allogeneic hematopoietic stem cell transplantation (HSCT) recipients. In 2009 serologic responses to either pandemic H1N1 (2009) vaccine (n = 36) or pandemic H1N1 (2009) infection (n = 2) were studied in 38 HSCT recipients. METHODS: Responses were measured with a standard hemagglutination-inhibition assay. Fourteen patients had active chronic graft-versus-host disease (cGvHD) at the time of vaccination/infection and seven patients had cGvHD in remission; 11 patients had no immunosuppressive therapy, and 27 patients were on immunosuppressive therapy. Nineteen patients (53%) responded to pandemic H1N1 (2009) vaccination. Two patients had pandemic H1N1 (2009) infection without prior vaccination, and one patient had severe pandemic H1N1 (2009) infection with acute respiratory distress syndrome despite prior single vaccination. RESULTS: Non-responders to pandemic H1N1 (2009) vaccination more often had cGvHD (65 vs. 53%) and received second- or third-line therapy (53 vs. 11%), while responders mostly had first-line therapy for cGvHD. While vaccine responders had no or single agent immunosuppressive therapy, non-responders frequently received moderate or intense immunosuppressive therapy. All vaccine recipients previously treated with rituximab were non-responders. CONCLUSIONS: In summary, the overall response to pandemic H1N1 (2009) vaccination in HSCT recipients was modest. Patients receiving combined immunosuppressive therapy for steroid-refractory cGvHD barely responded to pandemic H1N1 (2009) vaccination.

[Preventive crisis management in general outpatient palliative care - prospectively cross-sectional study of General Practitioners in Eastern Bavaria]. / Vorbeugendes Krisenmanagement in der allgemeinen ambulanten Palliativversorgung. Prospektive Querschnittstudie bei Hausärzten in Ostbayern.

BACKGROUND: General out-patient palliative care (GOPC) must be integrated into the care of patients with life-limiting diseases. Aim of the study was to evaluate experiences of general practitioners concerning advance directives and palliative emergency sheets. METHODS: A self-provided survey was mailed to all general practitioners in Regensburg (cross-sectional study). Main outcome measures included responses regarding a palliative emergency sheet (PES) and a palliative emergency plan (PEP). The investigation period was four months. The analysis was performed using defined criteria (e. g. professional experience concerning palliative care patients, patients treated in nursing homes, patients with dementia). RESULTS: Sixty-nine questionnaires from 259 were analysed (response rate 27 %). 86 % of respondents named practical experience in the care of palliative patients, 46 % named theoretical knowledge in this field. 41 % and 40 % consider creating an advance directive for their practical work as important/very important (p = 0.004 concerning the treatment of more than five palliative care patients per three months). 52 % and 49 % regard a PES or a PEP to be relevant (PES median: 6.5, SD ± 2.7; PEP median: 6.5 SD ± 2.9; inter-group analysis p < 0.05). 94 % of respondents name the general practitioner to be suitable for creating an advance directive. CONCLUSION: In Germany, GOPC in end-of-life care is very important. This study shows that advance directives were declared as an important instrument for patients? autonomy. The sense of PES and PEP to ensure patients? autonomy, especially for acute emergency medical palliative care, must be better recognized. However, the increase in acceptance in the GOPC for such instruments must be disclosed. Further studies to investigate this problem are necessary.

Isolated cerebral manifestation of Epstein-Barr virus-associated post-transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation: a case of clinical and diagnostic challenges.

We present the case of a 49-year-old male patient with Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD) limited to the brain that occurred 6 months after allogeneic hematopoietic stem cell transplantation (HSCT). Clinical symptoms included mental confusion, ataxia, and diplopia. Magnetic resonance imaging (MRI) revealed cerebellar and periventricular lesions consistent with an inflammatory process. Cerebrospinal fluid (CSF) analysis, but not peripheral blood, was positive for EBV-DNA, but no malignant cells were found. Brain biopsy was not feasible because of low platelet counts. As we considered a diagnosis of either EBV-associated encephalitis or PTLD, the patient was treated with rituximab combined with antiviral therapy. However, the cerebral lesions progressed and follow-up CSF testing revealed immunoglobulin H clonality as evidence of a malignant process. Subsequent treatment attempts included 2 donor lymphocyte infusions (DLI). Despite treatment, the patient died from autopsy-proven PTLD within 8 weeks of the onset of symptoms. This case demonstrates the clinical and diagnostic challenges of primary cerebral PTLD in a patient following allogeneic HSCT.

Transmural penetration of intravenously applied microbubbles during contrast-enhanced ultrasound as a new diagnostic feature in patients with GVHD of the bowel.

GVHD is a common complication in patients after allo-SCT. Early detection is important because early therapy may improve the outcome. We evaluated contrast-enhanced ultrasound (CEUS) in patients with GVHD to assess typical imaging features. CEUS was performed in nine patients with histologically proven GVHD. As a control four healthy volunteers and six patients with Crohn's disease (CD) were examined. We employed a high-resolution multi-frequency transducer (6-9 MHz) with contrast harmonic imaging. After the injection of 2.4 mL SonoVue (Bracco, Milan, Italy) intravenously data were acquired and stored digitally. Regions of interest were manually placed over the surrounding mesenteric fat, bowel wall and bowel lumen. Maximum signal increase of each compartment was calculated. Patients with CD and GVHD showed significant contrast uptake in the bowel wall. In contrast to CD patients and healthy volunteers, patients with GVHD showed transmural penetration of microbubbles into the bowel lumen. We assume that the damaged gut mucosal barrier in GVHD enables the microbubbles to penetrate through the bowel wall into the bowel lumen. The penetration of microbubbles into the bowel lumen may serve as a novel diagnostic feature for GVHD if confirmed in controlled clinical trials.

Clinical experience with posaconazole prophylaxis--a retrospective analysis in a haematological unit.

Invasive fungal infections (IFI) are major causes of death in high-risk haematological patients receiving induction therapy for acute leukaemia or intensified immunosuppression due to acute or chronic graft-vs.-host disease (GvHD) following allogeneic stem cell transplantation (SCT). Recently, two randomised studies showed the efficacy of a posaconazole prophylaxis (PP) in these patients to prevent IFI. This prompted the strong recommendation for the use of PP in national and international guidelines. As we started PP in our leukaemia and transplantation unit in summer 2007, we retrospectively analysed the impact of PP on the incidence of possible, probable or proven IFI in this group of patients. Incidence of IFI according to the revised EORTC criteria, published in 2008, was reviewed retrospectively in a group of high-risk patients treated in our unit 1 year before the start of PP compared with the same group in the following year with PP. First analysis was performed on an intention-to-treat basis comparing patients during 1 year of PP with the same group of patients in the year before the start of PP. In a second, deeper analysis, patients were grouped for fluconazole or posaconazole irrespective of the time period the prophylaxis was given. In a first intent-to-treat analysis, 56 patients were analysed in the period without PP (noPP) compared with 34 patients in the period with PP. Overall IFI rates (possible, probable and proven IFI) were reduced from 47% (noPP group) to 35% (PP group). In a second analysis, only patients receiving either fluconazole or PP were analysed, resulting in 29 patients in the noPP group and 36 patients in the PP group. There was a reduction in overall IFI in the PP group especially in the acute myeloid leukaemia (AML) induction patients, but this does not reach statistical significance because of low patient numbers. However, initiation of antifungal therapy was significantly less frequent in AML induction patients in the PP group compared with the noPP group. Unfortunately, this does not result in reduced mortality rates, as mortality in the PP group is higher (15% vs. 7%) than in noPP patients because of double the number of patients with severe GvHD in the PP group. Both breakthrough infections were documented in this subgroup of patients. Our data, collected in every day clinical practice, add further evidence to the advantage of a PP strategy in this group of high-risk patients. However, more data are urgently needed to assess the impact of PP on the incidence and pattern of fungal infections and the strategies to be used in patients with persisting fever and pulmonary infiltrates receiving PP, especially in the setting of SCT and GvHD.

Interleukin-10 promotes NK cell killing of autologous macrophages by stimulating expression of NKG2D ligands.

Under inflammatory conditions, the pleiotropic cytokine interleukin-10 (IL-10) is released in many tissues. It mediates anti-inflammatory effects in particular by inhibiting the release of T helper type 1 (Th1) cytokines. In contrast, we show here that NK cell cytotoxicity against autologous macrophages is elevated if both cell types are cultured with IL-10. The expression of most activatory NK receptors is increased after culture in the presence of IL-10. On the other hand, macrophages cultured in the presence of IL-10 show elevated expression of the NKG2D ligands major histocompatibility complex (MHC) class 1-like molecules (MIC) - A and - B, as well as UL-16 binding proteins (ULBP) - ULBP-1, ULBP-2 and ULBP-3. By masking the interaction of NK cells with macrophages through interruption of the NKG2D receptor with its ligands, we could reverse the IL-10-induced lysis of macrophages. Our data therefore reveal that IL-10 may exert a novel immunomodulatory role by stimulating NKG2D ligand expression on macrophages, thereby rendering them susceptible to NK cell elimination. This suggests that NK cells would delete macrophages and potentially other immature antigen-presenting cells (APC) or their precursors under inflammatory conditions as a feedback mechanism to shut off uncontrolled immune responses.

Successful treatment of Scedosporium apiospermum soft tissue abscess with caspofungin and voriconazole in a severely immunocompromised patient with acute myeloid leukemia.

We report the case of a 53-year-old female patient with refractory acute myeloid leukemia developing a necrotic, soft tissue abscess on the right forearm caused by Scedosporium apiospermum during prolonged severe neutropenia (absolute white blood cell count <500/µL for 49 days). In the context of the severely immunocompromised state of the patient and her need for allogeneic hematopoietic stem cell transplantation (HSCT), surgical treatment options were not favored. Therefore, combined antifungal therapy with voriconazole and caspofungin was started, based on the results of the in vitro testing (minimum inhibitory concentrations of voriconazole, posaconazole, and amphotericin B: 1, 4, and >2mg/L, respectively). The local site of infection slowly improved clinically and no spread of S. apiospermum infection to other sites was observed. After HSCT, the soft tissue abscess resolved completely and the patient has remained free of S. apiospermum infection since then. We successfully demonstrate that the use of combined antifungal therapy with voriconazole and casopfungin may further improve the clinical course and provides a promising therapeutic option to treat Scedosporium infections in such patients.

Modular therapy approach in metastatic castration-refractory prostate cancer.

PURPOSE: The present multi-center phase II study was designed to support the hypothesis that networking agents, which bind to ubiquitous accessible targets in metastatic castration-refractory prostate cancer (CRPC) may counteract neoplasia-specific aberrant cellular functions, thereby mediating PSA response (primary endpoint). METHOD: Patients with metastatic CRPC received low-dose chemotherapy with capecitabine 1 g twice daily plus dexamethasone 1 mg daily for 14 days every 3 weeks, COX-2 blockade with rofecoxib 25 mg (or etoricoxib 60 mg) daily combined with pioglitazone 60 mg daily until disease progression. RESULTS: Thirty-six consecutive patients with metastatic CRPC were enrolled, of whom n = 18 (50%) had been extensively pretreated with radio- or radionuclid therapy and n = 16 (44%) with chemotherapies; n = 8 patients (22%) were medically none-fit, having an ECOG-score of 0-2. Nine of 15 patients with PSA response >50% showed objective response. Median time to PSA response was 2.4 months (range 1.0-7.3 months). Two of 9 patients responding with PSA < 4 ng/ml showed complete resolution of skeletal lesions after 9 and 16 months; 13 patients had a stable course of disease, and 5 patients experienced progressive disease. Median progression-free survival (PFS) was 4.0 months (2.8-5.1 months) and median overall survival (OS) 14.4 months (10.7-17.2 months). Toxicities according to WHO grade II were noticed in 9 patients. CONCLUSIONS: This new combined modular therapy approach is able to induce major responses including resolution of skeletal lesions in patients with CRPC. Furthermore, the study may clinically support the above-mentioned hypothesis.

Recipient NOD2/CARD15 status affects cellular infiltrates in human intestinal graft-versus-host disease.

Nucleotide-binding oligomerization domain 2/caspase recruitment domain 15 (NOD2/CARD15) polymorphisms have been identified as risk factors of both Crohn's disease and graft-versus-host disease (GVHD) following allogeneic stem cell transplantation. However, the role of these receptors of innate immunity in the pathophysiology of gastrointestinal GVHD is still poorly defined. Immunohistological features of intestinal GVHD were analysed in gastrointestinal biopsies from 58 patients obtained at the time of first onset of intestinal symptoms. The observed changes were correlated with concomitant risk factors and the presence of polymorphisms within the pathogen recognition receptor gene NOD2/CARD15. Intestinal GVHD was associated with a stage-dependent decrease in CD4 T cell infiltrates and an increase in CD8 T cells in the lamina propria; CD8 infiltrates correlated with extent of apoptosis and consecutive epithelial proliferation. The presence of NOD2/CARD15 variants in the recipient was associated with a significant loss of CD4 T cells: in a semiquantitative analysis, the median CD4 score for patients with wild-type NOD2/CARD15 was 1.1 (range 3), but only 0.4 (range 2) for patients with variants (P = 0.002). This observation was independent from severity of GVHD in multivariate analyses and could not be explained by the loss of forkhead box P3(+) T cells. Our results suggest a loss of protective CD4 T cells in intestinal GVHD which is enhanced further by the presence of NOD2/CARD15 variants. Our study might help to identify more selective therapeutic strategies in the future.

Chemokine and chemokine receptor expression analysis in target organs of acute graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic bone marrow transplantation (allo-BMT), and infiltration of donor leukocytes into aGVHD target organs is partially orchestrated by chemokines. Using a murine BMT model, the expression of 30 chemokines or chemokine receptors in the lung, liver, gut and tongue was analyzed using real-time PCR at 1, 2, 3 and 6 weeks after BMT during the development of clinical aGVHD and target organ histopathology. CXCL9-11 expression was linked to elevated expression of CXCR3 in the gut, lung and tongue. In contrast, hepatic CXCR3 expression was not changed, whereas a clear association was seen for CXCL16 and CXCR6 expression. An elevated intestinal CCL3 expression 1 week after allo-BMT was associated with an increased expression of CCR5 but not CCR1 or CCR3, and in the lung and liver CCL3-CCL5 expression was associated with increases in CCR1 and CCR5. Overexpression of CCL2, CCL8, CCL12 and their receptor CCR2 was found in the liver and lung, but not in the gut and tongue. On the basis of the differences in kinetics and organ distribution, more studies are required to better characterize specific targets within this network, as this will allow the development of novel preventive and therapeutic approaches by using single or multiple targeting reagents.

EPO in combination with G-CSF improves mobilization effectiveness after chemotherapy with ifosfamide, epirubicin and etoposide and reduces costs during mobilization and transplantation of autologous hematopoietic progenitor cells.

A successful stem cell harvest is a prerequisite for peripheral blood SCT. We investigated the number of CD34(+) cells mobilized, the number of leukaphereses needed and the expenses of treatment for 28 patients with multiple myeloma randomly assigned to receive either G-CSF alone or G-CSF+EPO for stem cell mobilization after chemotherapy with ifosfamide, epirubicin and etoposide. All patients treated with G-CSF+EPO reached the threshold of 6 x 10(6) CD34(+) cells per kg body weight (kgbw), with a mean of 1.3 leukaphereses. On average 15.4 x 10(6) CD34(+) cells/kgbw were collected. In the G-CSF-alone group, the mean number of leukaphereses was 1.8, and 12.6 x 10(6) CD34(+) cells/kgbw were collected, and two patients failed the threshold. Overall costs per patient for mobilization and leukaphereses were 8339 euro (G-CSF+EPO) and 8842 euro (G-CSF). After transplantation, fewer blood transfusions (0.6 versus 1.3, P=0.05), fewer days on antibiotics (2.3 versus 6.1, P=0.02) and a shorter hospital stay (15.2 versus 17.8, P=0.06) were noted in the G-CSF+EPO group resulting in a 19.2% reduction of costs for each transplant (P=0.018). In summary, EPO improves the mobilization efficiency of G-CSF and so reduces costs of mobilization and SCT.

The role of genetic variants of NOD2/CARD15, a receptor of the innate immune system, in GvHD and complications following related and unrelated donor haematopoietic stem cell transplantation.

Previous studies from our group indicated a role of SNPs within the innate immunity receptor NOD2/CARD15 as a risk factor for GvHD and treatment-related mortality allogeneic stem cell transplantation from HLA-identical siblings. We now extended these studies to assess the role of NOD2/CARD15 SNPs in 342 unrelated donor transplants. Overall, presence of any SNPs in patients or donor resulted in an increased risk of severe GvHD (25% in wildtype versus 38% in recipients and donors with variants, P= 0.01), which did not translate in increased mortality. When the analysis was broken down to individual SNPs, the presence of a SNP13 in the donor turned out to be the only highly significant risk factor (GvHD III/IV 22% wt, 42% SNP13 donor, P < 0.004; TRM 33% wt versus 59% SNP13 donor, P= 0.01; overall survival 49% wt versus 26% SNP13 donor, P= 0.007). This association was confirmed in multivariate analysis. Analysis of clinical risk factors suggested that this effect was most prominent in patients receiving any form of T cell depletion. Thus our observation indicates that the presence of a defect in innate immunity signalling in donor monocytes and possibly antigen presenting cells is most prominent in patients having additional T cell deficiency.