Treatment approach in patients with hyperbilirubinemia secondary to liver metastases in gastrointestinal malignancies: a case series and review of literature.

BACKGROUND: Treatment of patients with severe liver dysfunction including hyperbilirubinemia secondary to liver metastases of gastrointestinal (GI) cancer is challenging. Regimen of oxaliplatin and fluoropyrimidine (FP)/folinic acid (FA) ± a monoclonal antibody (moAb), represents a feasible option considering the pharmacokinetics. Clinical data on the respective dosage and tolerability are limited and no recommendations are available. METHODS: Consecutive patients with severe hyperbilirubinemia [>2 × upper limit of the normal range (ULN) and >2.4 mg/dl] due to liver metastases of GI cancer without options for drainage receiving oxaliplatin, FP/FA ± moAb were analyzed. To collect further data a review of the literature was performed. RESULTS: A total of 12 patients were identified between 2011 and 2015. At treatment start, median bilirubin level was 6.1 mg/dl (>5 × ULN, range 2.7-13.6). The majority of patients (n = 11) received dose-reduced regimen with oxaliplatin (60-76%) and FP/FA (0-77%), rapidly escalating to full dose regimen. During treatment, bilirubin levels dropped more than 50% within 8 weeks or normalized within 12 weeks in 6 patients (responders). Median overall survival was 5.75 months (range 1.0-16.0 months) but was significantly prolonged in responders compared to nonresponders [9.7 and 3.0 months, p = 0.026 (two-sided test); 95% confidence interval (CI): 1.10-10.22]. In addition, case reports or series comprising a further 26 patients could be identified. Based on the obtained data a treatment algorithm was developed. CONCLUSION: Treatment with oxaliplatin, FP/FA ± moAb is feasible and may derive relevant benefits in patients with severe liver dysfunction caused by GI cancer liver metastases without further options of drainage.

Radiotherapy for SMAD4-negative musculoskeletal lesions from pancreatic cancer: case report and review.

BACKGROUND: Pancreatic cancer (PC) predominantly metastasizes to liver, lung, and peritoneum. Metastatic disease correlates with SMAD4 status. Musculoskeletal metastases (MSM) are rare in pancreatic cancer. The role of radiation therapy (RT) in patients with musculoskeletal metastases is not clear. METHODS: We present a case of a woman with musculoskeletal metastases of PC evolving 4 years after Whipple's procedure and adjuvant therapy. She was treated with RT for 7 MSM. Radiation dose was 15-45 Gy, delivered in doses of 2.5-5 Gy per fraction. SMAD4 status was examined by immunohistochemistry. Furthermore we undertook a review of the literature to examine the value of RT in musculoskeletal metastasis of PC. RESULTS: In the presented patient we treated 7 MSM of SMAD4-mutant PC with RT. RT achieved local control in 4 of the 7 MSM. At the resection margin of one MSM recurrent tumor was observed after RT. The status of one MSM was unknown and one MSM showed local progression. Follow-up revealed progression of pain in 1 of the 7 MSM. Except of hyperpigmentation no side effects occurred. There was no dose-correlation effect on tumor control observed. A review of the literature showed that a musculoskeletotrophic phenotype of metastases is rare in PC. MSM of PC are rapidly increasing soft tissue masses causing pain and loss of anatomical function. RT as a treatment option for musculoskeletal metastasis is described in the current literature in only 2 cases. Radiotherapy aims to achieve local control, pain relief, and to maintain anatomical function. CONCLUSION: Radiotherapy is an effective and well-tolerated approach for multiple musculoskeletal metastases of PC.

Adaptive Resistance to Immunotherapy Directed Against p53 Can be Overcome by Global Expression of Tumor-Antigens in Dendritic Cells.

Immunotherapy of cancer utilizes dendritic cells (DCs) for antigen presentation and the induction of tumor-specific immune responses. However, the therapeutic induction of anti-tumor immunity is limited by tumor escape mechanisms. In this study, immortalized dendritic D2SC/1 cells were transduced with a mutated version of the p53 tumor suppressor gene, p53M234I, or p53C132F/E168G, which are overexpressed in MethA fibrosarcoma tumor cells. In addition, D2SC/1 cells were fused with MethA tumor cells to generate a vaccine that potentially expresses a large repertoire of tumor-antigens. Cellular vaccines were transplanted onto Balb/c mice and MethA tumor growth and anti-tumor immune responses were examined in vaccinated animals. D2SC/1-p53M234I and D2SC/1-p53C132F/E168G cells induced strong therapeutic and protective MethA tumor immunity upon transplantation in Balb/c mice. However, in a fraction of immunized mice MethA tumor growth resumed after an extended latency period. Analysis of these tumors indicated loss of p53 expression. Mice, pre-treated with fusion hybrids generated from D2SC/1 and MethA tumor cells, suppressed MethA tumor growth and averted adaptive immune escape. Polyclonal B-cell responses directed against various MethA tumor proteins could be detected in the sera of D2SC/1-MethA inoculated mice. Athymic nude mice and Balb/c mice depleted of CD4(+) or CD8(+) T-cells were not protected against MethA tumor cell growth after immunization with D2SC/1-MethA hybrids. Our results highlight a potential drawback of cancer immunotherapy by demonstrating that the induction of a specific anti-tumor response favors the acquisition of tumor phenotypes promoting immune evasion. In contrast, the application of DC/tumor cell fusion hybrids prevents adaptive immune escape by a T-cell dependent mechanism and provides a simple strategy for personalized anti-cancer treatment without the need of selectively priming the host immune system.

Omalizumab treatment of systemic mast cell activation disease: experiences from four cases.

We report on the outcome of 4 patients with therapy-resistant systemic mast cell activation disease (MCAD) treated with the anti-IgE monoclonal antibody omalizumab in compassionate use. Two patients achieved an impressive persistent clinical response to treatment with omalizumab. In the third patient symptoms gradually improved. In the fourth patient omalizumab treatment had to be discontinued due to intolerable mast cell mediator-induced symptoms. In conclusion, omalizumab can lessen the intensity of the symptoms of systemic MCAD. Hence, omalizumab should be considered as a therapeutic option in cases of systemic MCAD that are resistant to evidence-based therapy.

c-kit (CD117) expression in human tumors and its prognostic value: an immunohistochemical analysis.

c-kit functions as a tyrosine kinase receptor and represents a target for small molecule kinase inhibitors. The expression pattern for c-kit was studied in different human tumor types to their correlation with prognosis. Paraffin-embedded tumor tissues from 282 patients were analyzed immunohistochemically for c-kit expression. Survival and follow-up data were available from 192/282 (68%) patients. c-kit immunopositivity was found in 62/282 (22%) cases. c-kit expression was found in 14/83 (17%) colorectal cancers, in 13/62 (21%) breast cancers, in 7/20 sarcomas (35%), in 5/14 (36%) renal cell carcinomas, in 2/12 ovarian cancers (17%) and in 2/12 (17%) hepatocellular carcinomas. We found no significant correlation between c-kit expression and prognosis although a trend to a worse prognosis in patients with c-kit positive tumors could be observed. Expression of c-kit was found in tumor samples with varying intensities and infrequently.

Tumour Biology: tumour-associated inflammation versus antitumor immunity.

The latest research results suggest that tumour-infiltrating leukocytes and the intra-tumoural cytokine environment play a central role in both the genesis and development of cancer. Over a hundred years ago, Virchow pointed out that numerous immune cells occur in the vicinity of practically all malignant tumours and that the structure of tumour tissue closely resembles the inflamed region of a non-healing wound. With the aid of the latest molecular and cell-biological methods, we are not only able today to closely characterise tumour cells and their immediate vicinity but also the other cell types present in tumour tissue, such as infiltrating immune cells, endothelial cells, connective tissue cells and others, both in terms of phenotype and function. In addition, there is growing understanding of the significance of the composition and functioning of endogenous messenger substances such as cytokines, chemokines and prostaglandins in healthy and malignantly altered tissues. From the immunological point of view, the main characteristics are dysregulated inflammatory conditions caused by the tumour cells themselves or by external factors, depending on the type of tumour event. It is evident that prolonged dysregulated inflammatory conditions favour not only carcinogenesis but also the local infiltration and metastasis of malignantly modified cells and counteract the development of efficient antitumor immunity. On the other hand, there are indications that through the polarisation of immunological reactions, the ability of immunological regulator and effector cells to induce efficient antitumor immunity can be modulated. Within the framework of this summary, the essential immunological aspects of tumour formation and tumour development known at present are presented and possible new therapeutic strategies are discussed.

DNA vaccination with a mutated p53 allele induces specific cytolytic T cells and protects against tumor cell growth and the formation of metastasis.

PURPOSE: Genetic vaccination by expression plasmids that encode mutant p53 was conducted to characterize exogenously induced anti-tumoral immunity in mice. METHODS: Gene transfer was evaluated by reporter gene expression assays. The efficacy of genetic immunization was addressed by analysis of solid tumor outgrowth and the formation of metastases. Cell mediated immunity was determined by (51)Cr-release cytotoxicity assays and adoptive lymphocyte transfer experiments. RESULTS: Genetic vaccination resulted in a persistent protection against the growth and metastasis of transplanted tumor cells. Immunoprotection was based on the induction of cytolytic T cells (CTLs) able to recognize mutant but not wild type p53. Mice were not protected from tumor cell growth when the tumor cells expressed alternate p53 mutations or overexpressed wild type p53. No p53 specific humoral immune response was detected. T-lymphocyte transfer experiments demonstrated that resistance to tumor growth depended both on tumor size and a time-dependent induction of protective immunity. Small tumors (Ø < 0.4 cm(3)) went into remission or remained stable upon adoptive transfer of T-lymphocytes from mice immunized with mutant p53 DNA; larger tumors progressed. A time course of immunization was evaluated and showed that DNA vaccination must precede tumor cell inoculation in order to induce an efficient anti-tumoral response. CONCLUSION: DNA vaccination against the mutated form of p53 can elicit a specific adaptive immune response and has anti-tumoral activity. Tumor burden and the time necessary to acquire tumor immunity were recognized as critical parameters for immunization; however, tumors may evade specific immunotherapy.

IFN-y enhances T(H)1 polarisation of monocyte-derived dendritic cells matured with clinical-grade cytokines using serum-free conditions.

Using serum-free conditions, human monocyte-derived dendritic cells (MoDCs) tend to mature insufficiently in a T(H)1-polarizing direction under approved and standardized clinical conditions. However, for the initiation of an efficient tumour antigen-specific cytotoxic T-cell response, the induction of a distinct T(H)1 response is favourable. Therefore, to improve T(H)1 polarisation, the influence of interferon-gamma (IFN-gamma) on the maturation of MoDCs was investigated with clinical-grade cytokines or lipopolysaccharide (LPS) in serum-free medium focusing on the viability, phenotypic characteristics, cytokine profile and restimulating capacities. As in previous research, we confirmed that in respect of viability and phenotypic characteristics, cytokine cocktails consisting of tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6 and prostaglandin (PG) E2, mature MoDCs most efficiently. However, these cytokine-matured MoDCs secreted relatively high levels of IL-10 and only low levels of IL-12p70. Remarkably, if IFN-gamma was added, significantly lower levels of IL-10 concomitant with higher levels of IL-12p70 could be detected. Pretreatment with IFN-gamma did not improve the phenotypic characteristics nor the T(H)1 polarisation of MoDCs. Nevertheless, MoDCs matured with clinical-grade cytokines and IFN-gamma could be re-stimulated most effectively with IFN-gamma. In conclusion, our work demonstrates that addition of INF-gamma to clinical-grade cytokine cocktails readily matures MoDCs and enhances their T(H)1 polarisation efficiently under serum-free conditions.

Treatment of anthracycline extravasation with dexrazoxane -- clinical experience.

BACKGROUND: Accidental extravasation is a severe complication when administering anthracyclines. We describe 3 cases of extravasation with 3 different anthracyclines. PATIENTS AND METHODS: One patient came from another hospital for a second opinion after an epirubicin extravasation. Only surgical debridement of the necrotic tissue was possible. The other two extravasations occurred during treatment with doxorubicin and doxorubicin- EMCH, respectively, in our department. Both patients were treated with dexrazoxane within 6 h of the event. RESULTS: The 2 patients treated with dexrazoxane recovered completely without any sequelae. CONCLUSIONS: Treatment of antracycline extravasation with dexrazoxane is potentially useful and safe.

Cytotoxic efficacy and influence on cellular phospholipid metabolism of 2-hydroxy- and 2-O-acetyl-octadecylphosphocholines.

The cytotoxic efficacy and influence on phospholipid composition of the new alkylphosphocholines (APC) 2-hydroxy and 2-O-acetyl-octadecylphosphocholines both synthesised in R- and S-configuration (R/S-OH and R/S-O-acetyl) were examined in vitro using HL-60 and MDA-MB-468 cells. IC50- and LC50-values were measured by MTT- and cell count assay. All tested APC showed higher or similar cytotoxic efficacy compared to the well known APC hexadecylphosphocholine (HePC). However, while S-configured APC (IC50) revealed considerably higher cytotoxic activities, only R- (natural)-configured APC caused significant changes in the phospholipid composition of tumour cells. Further investigations revealed an increase in R-O-acyl and loss of PC up to 70% in the membrane of both cell lines. Similar to PC, R-O-acyl bears two long non-polar hydrocarbon chains and stabilises cell membranes structurally, thus, possibly explaining less cytotoxicity and lack of apoptosis induction by R-configured APC. Nevertheless, an enrichment of R-O-acyl up to 70% at the expense of PC in cell membrane is tremendous and may inhibit tumour development by influencing the intracellular lipid signalling. In conclusion, our findings reveal the antitumoral efficacy of all tested new APC and offer new perspectives in drug development targeting phospholipid metabolism.

Regression of cutaneous tumor lesions in patients intratumorally injected with a recombinant single-chain antibody-toxin targeted to ErbB2/HER2.

ScFv(FRP5)-ETA is a recombinant single-chain antibody-toxin with binding specificity for ErbB2/HER2. Previously potent antitumoral activity of the molecule against ErbB2 overexpressing tumor cells was demonstrated in vitro and in animal models. Here we report on the first application of scFv(FRP5)-ETA in human cancer patients summarizing case reports collected in four different clinical centers. Eleven patients suffering from metastatic breast and colorectal cancers and from malignant melanoma were treated on a compassionate-use basis by intratumoral injection of scFv(FRP5)-ETA into cutaneous lesions once daily for 7-10 days. Total daily doses ranged from 60 to 900 microg, and total doses per treatment cycle ranged from 0.6 to 6.0 mg. Treatment caused injected tumors to shrink in six of the 10 cases evaluated (60%). Complete regression of injected tumor nodules was accomplished in four patients (40%) and partial reduction in tumor size in another two patients (20%). Adverse reactions were restricted to local symptoms such as pain and inflammation at injection sites which were fully reversible. Only in one patient treated at the highest daily doses systemic liver toxicity of grade 2 was observed and treatment was discontinued on day 7. No hematologic, renal, and/or cardiovascular toxicities were noted. Our results demonstrate that local therapy with scFv(FRP5)-ETA can be effective against ErbB2 expressing tumors justifying further clinical development of this reagent.