Effects of an EGFR-binding affibody molecule on intracellular signaling pathways.

Effects on intracellular signaling were studied in cells treated with the affibody molecule (ZEGFR:955)2 that targets the epithelial growth factor receptor (EGFR). EGFR is overexpressed in many types of cancers and plays a fundamental role in cell signaling and it is of interest to find targeting agents capable of blocking the receptor. The clinically approved antibody cetuximab (Erbitux) and the natural ligand EGF were included as reference molecules.

Quantification of internalization of EGFR-binding Affibody molecules: Methodological aspects.

Tumor cell internalization of targeting agents is of interest, since internalization influences the local retention time of a radionuclide and thereby imaging quality in PET and SPECT and effects of radionuclide therapy. In cases where nuclear methods are not applicable at the cellular level, quantitative fluorescent techniques are useful as described in this article. Two fluorescence-based methods to study cellular internalization were applied: the CypHer and the Alexa488-quenching methods, both utilized in fluorescence microscopy and flow cytometry.

Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer.

Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1.

Insulin-heparin infusions peritransplant substantially improve single-donor clinical islet transplant success.

Background: Successful islet transplantation can result in insulin independence in many patients with type 1 diabetes mellitus, but it often requires more than one islet infusion. The ability to achieve insulin independence with a single donor is an important goal in clinical islet transplantation due to the limited organ supply.

Methods: We examined factors that may be associated with insulin independence after islet transplantation with islets from a single donor, using univariate and multivariate analysis.

Hsp90 as a therapeutic target in patients with oesophageal carcinoma.

Importance Of The Field: Oesophageal carcinoma has a poor prognosis with a 5-year overall survival rate of only 10 - 20%. The disease is often diagnosed at a late stage, when dissemination may already have occurred, contributing to the poor prognosis. However, recent developments in targeted therapy now offer new possibilities in the treatment arsenal.

A new oxygen carrier for improved long-term storage of human pancreata before islet isolation.

Background: Pancreas oxygenation during cold storage has been established in islet isolation and transplantation to prevent ischemic tissue damage using perfluorodecalin (PFD) as hyperoxygen carrier. However, studies in humans and pigs provided conflicting results about the efficiency of PFD for pancreas oxygenation. The aim of this study was to compare PFD with a newly developed oxygen carrier composed of perfluorohexyloctane and polydimethylsiloxane 5 (F6H8S5) for long-term storage of human pancreata.

A low-dose hypersensitive keratinocyte loss in response to fractionated radiotherapy is associated with growth arrest and apoptosis.

Background And Purpose: The existence of a hypersensitive radiation response to doses below 0.5Gy is well established for many normal and tumour cell lines. There is also evidence for hypersensitive tissue responses in acute skin damage and kidney function in mice.

A window of opportunity phase II study of enzastaurin in chemonaive patients with asymptomatic metastatic colorectal cancer.

Background: Preclinically, protein kinase C and AKT activation can be inhibited by enzastaurin and reduce tumor growth of colorectal cancer cells. In asymptomatic patients with metastatic colorectal cancer (mCRC), enzastaurin activity was evaluated by measuring the 6-month progression-free survival (PFS) rate in a window study design.

Patients And Methods: Chemonaive patients with asymptomatic mCRC who did not require immediate chemotherapy-induced tumor reduction received a 400-mg thrice daily loading dose of enzastaurin on day 1 of cycle 1, followed by 500 mg once daily for the remaining 28-day cycles.

Complement activation by CpG in a human whole blood loop system: mechanisms and immunomodulatory effects.

Phosphorothioate oligodeoxynucleotides can activate complement, and experimental murine studies have revealed differential effects upon simultaneous TLR stimulation and complement activation compared with either event alone. We set out to investigate the immune stimulatory effects of CpG 2006 in fresh non-anticoagulated human blood with or without presence of active complement. We also sought to elucidate the mechanism behind complement activation upon stimulation with phosphorothioate CpG 2006.

Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data.

Purpose: Depletion of cellular nicotinamide adenine dinucleotide (NAD) by inhibition of its synthesis is a new pharmacological principle for cancer treatment currently in early phases of clinical development. We present new and previously published data on the safety and efficacy of these drugs based on early clinical trials.

Methods: A phase I clinical trial of CHS 828 in patients with advanced solid tumours was performed.

Modeling silicon diode energy response factors for use in therapeutic photon beams.

Silicon diodes have good spatial resolution, which makes them advantageous over ionization chambers for dosimetry in fields with high dose gradients. However, silicon diodes overrespond to low-energy photons, that are more abundant in scatter which increase with large fields and larger depths. We present a cavity-theory-based model for a general response function for silicon detectors at arbitrary positions within photon fields.

Individualized dosimetry in patients undergoing therapy with (177)Lu-DOTA-D-Phe (1)-Tyr (3)-octreotate.

Purpose: In recent years, targeted radionuclide therapy with [(177)Lu-DOTA(0), Tyr(3)]octreotate for neuroendocrine tumours has yielded promising results. This therapy may be further improved by using individualized dosimetry allowing optimization of the absorbed dose to the tumours and the normal organs. The aim of this study was to investigate the feasibility and reliability of individualized dosimetry based on SPECT in comparison to conventional planar imaging.

gammaH2AX and cleaved PARP-1 as apoptotic markers in irradiated breast cancer BT474 cellular spheroids.

Chemo- and radiotherapy induce apoptosis in tumours and surrounding tissues. In a search for robust and reliable apoptosis markers, we have evaluated immunostaining patterns of gammaH2AX and cleaved PARP-1 in paraffin-embedded cellular spheroids. Breast cancer BT474 cells were grown as cell spheroids to diameters of 700-800 microm.

Evaluation of the Hsp90 inhibitor NVP-AUY922 in multicellular tumour spheroids with respect to effects on growth and PET tracer uptake.

Background: Molecular targeting has become a prominent concept in cancer treatment and heat shock protein 90 (Hsp90) inhibitors are suggested as promising anticancer drugs. The Hsp90 complex is one of the chaperones that facilitate the refolding of unfolded or misfolded proteins and plays a role for key oncogenic proteins such as Her2, Raf-1, Akt/PKB, and mutant p53. NVP-AUY922 is a novel low-molecular Hsp90 inhibitor, currently under clinical development as an anticancer drug.

Molecular characterization of the stomach microbiota in patients with gastric cancer and in controls.

Persistent infection of the gastric mucosa by Helicobacter pylori can initiate an inflammatory cascade that progresses into atrophic gastritis, a condition associated with reduced capacity for secretion of gastric acid and an increased risk of developing gastric cancer. The role of H. pylori as an initiator of inflammation is evident but the mechanism for development into gastric cancer has not yet been proven.

Radiation to supraclavicular and internal mammary lymph nodes in breast cancer increases the risk of stroke.

The aim of this study was to assess whether adjuvant treatment of breast cancer (BC) affects the risk of stroke, and to explore radiation targets and fraction doses regarding risk and location of stroke. In a Swedish BC cohort diagnosed during 1970-2003, we carried out a nested case-control study of stroke after BC, with relevant details extracted from medical records. The odds ratio (OR) for radiotherapy (RT) vs that of no RT did not differ between cases and controls (OR=0.

Iodinated contrast media decrease renomedullary blood flow. A possible cause of contrast media-induced nephropathy.

The renal medulla has been implicated as a key target for contrast media-induced nephropathy (CIN). Although the effects of contrast media (CM) on whole kidney blood flow are well characterized, the effect of CM on renal medullary blood flow has been controversial. It has been reported that an extremely high dose of a high osmolar CM (iothalamate; 2900 mg I/kg bw) injected rapidly increased the renal outer medullary blood flow (OMBF).

An explorative randomised phase II study of sequential chemotherapy in advanced upper gastrointestinal cancer.

The feasibility, safety, and efficacy of planned sequential administration of docetaxel and irinotecan with 5-fluorouracil (5-FU)/leucovorin in advanced upper gastrointestinal adenocarcinoma (UGIA) are unknown. Seventy-three patients with gastric (GC; n = 22), pancreatic (PC; n = 28) or biliary cancer (BC; n = 23) were randomised to start with 45 mg/m(2) docetaxel or 180 mg/m(2) irinotecan combined with 5-FU/leucovorin every 2nd week. After every 2nd course, the patients were crossed over to the other combination.

The importance of tryptic-like activity in purified enzyme blends for efficient islet isolation.

Background: The isolation of islets from the human pancreas critically depends on an efficient enzyme blend. Previous studies have solely focused on the presence of collagenase and neutral protease/thermolysin. Despite improved characterization of these components, the lot-related variability in efficacy still persists suggesting that additional so far disregarded enzymes are required for efficient islet cleavage.

Hsp90 is expressed and represents a therapeutic target in human oesophageal cancer using the inhibitor 17-allylamino-17-demethoxygeldanamycin.

Heat shock protein 90 (Hsp90) has been demonstrated to protect oncogenic variants of signalling molecules from degradation and may consequently serve as a therapeutic target for the treatment of oesophageal cancer for which adequate therapy is often lacking. We studied the expression of Hsp90 in tumour tissues of human oesophageal cancer and the impact of Hsp90 inhibition on oesophageal cancer cell lines using the drug 17-allylamino-17-demethoxygeldanamycin (17-AAG). Quantitative immunohistochemistry was performed on formalin-fixed paraffin-embedded tissues from patients with oesophageal cancer.

Cancer of the parotid gland; long-term follow-up. A single centre experience on recurrence and survival.

Background: The aim of the study was to investigate the results of treatment of malignant parotid gland tumours at a single centre during a 56 year period, focusing on tumour control and survival.

Patients And Methods: At Uppsala University Hospital, Sweden, 144 patients (73 male and 71 female) with parotid cancer were treated between 1948 and 2004. The mean and median ages were 62 and 65 years, respectively (range 16-89 years).

Health-related quality of life and distress in cancer patients: results from a large randomised study.

To compare the effectiveness of individual support, group rehabilitation and a combination of the two in improving health-related quality of life (HRQOL) and psychological well-being in cancer patients during 24 months after diagnosis, as compared with standard care (SC). Furthermore, to compare the study sample and a random sample of the Swedish population with regard to HRQOL. A total of 481 consecutive patients, newly diagnosed with cancer, were randomly assigned to one of the four alternatives.

Dimeric HER2-specific affibody molecules inhibit proliferation of the SKBR-3 breast cancer cell line.

HER2-specific affibody molecules in different formats have previously been shown to be useful tumor targeting agents for radionuclide-based imaging and therapy applications, but their biological effect on tumor cells is not well known. In this study, two dimeric ((Z(HER2:4))(2) and (Z(HER2:342))(2)) and one monomeric (Z(HER2:342)) HER2-specific affibody molecules are investigated with respect to biological activity. Both (Z(HER2:4))(2) and (Z(HER2:342))(2) were found to decrease the growth rate of SKBR-3 cells to the same extent as the antibody trastuzumab.

Chemotherapy in addition to preoperative radiotherapy in locally advanced rectal cancer - a systematic overview.

The value of chemotherapy with radiotherapy has been explored in recent randomised clinical trials in locally advanced rectal cancer (LARC). An overview of these trials was made together with a discussion of what constitutes LARC. Although imaging is required for adequate staging of primary rectal cancer, the term 'locally' advanced has no consistent definition and has been used differently in the trials.