A man in his forties with increasing shortness of breath. / En mann i 40-årene med økende pustevansker.

BACKGROUND: Diffuse large B-cell lymphoma is an aggressive non-Hodgkin lymphoma. The patients are often critically ill with a variety of symptoms, but the disease is potentially curable. CASE PRESENTATION: A previously healthy man in his forties was admitted to the local hospital feeling unwell, with dyspnoea, cough, fever and weight loss. The clinical examination was normal. Lactate dehydrogenase and sedimentation rate were elevated. Blood smear and bone marrow biopsy were normal. In the weeks that followed, the patient became critically ill with respiratory failure, exhaustion and continuous fever. Computed tomography (CT) scan revealed diffuse lung infiltrates in addition to hepatosplenomegaly. High levels of ferritin, triglycerides and soluble interleukin-2 receptor were also found. Haemophagocytic lymphohistiocytosis was suspected, and the patient was admitted to the intensive care unit. Biopsies confirmed diffuse large B-cell lymphoma, and treatment was started immediately. INTERPRETATION: The clinical manifestations of lymphoma are diverse. In this case report the suspicion of haemophagocytic lymphohistiocytosis led to a thorough search for a malignant disease, primarily lymphoma. Patients with diffuse large B-cell lymphoma are often critically ill, deteriorating rapidly. Histological verification of the diagnosis and immediate start of treatment are essential for the outcome.

Anaplastic large cell lymphoma, ALK-negative of the breast diagnosed a short time after removal of breast implant in a patient with breast carcinoma: diagnostic and therapeutic considerations.

A case of mass-forming breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) with onset a short time after explanation of the cosmetic prosthesis is reported. The cause of implant removal was carcinoma diagnosed in the ipsilateral breast. The rarity of an almost synchronous manifestation of BIA-ALCL and breast carcinoma and the diagnostic challenges of mass-forming BIA-ALCL in a previously operated breast substantiate this report. The clinical course, diagnostic workup and therapeutic considerations are presented and discussed in detail. This case shows that a diagnosis of BIA-ALCL must always be considered even without a prosthesis in place in patients with a long history of textured implants.

Androgen substitution with testosterone undecanoate in survivors of bilateral testicular cancer requires individually-adjusted injection intervals.

OBJECTIVES: • To explore the efficacy and safety of testosterone undecanoate (TU) (Nebido®; Bayer Schering Pharma AG, Berlin, Germany) in patients with bilateral germ cell testicular cancer (GCTC) who have switched androgen substitution from testosterone enanthate (Primoteston Depot®, Bayer Schering Pharma AG). PATIENTS AND METHODS: • In total, 47 bilaterally orchidectomized GCTC patients were included in a prospective study to monitor serum gonadal hormones, biochemical safety and symptoms of hypogonadism based on the Aging Males' Symptoms scale during TU treatment for a 28-week period. RESULTS: • During treatment, serum levels of total (TT) and calculated free testosterone (CFT) increased with simultaneously decreasing levels of FSH and LH. However, considerable variations in median levels of TT and CFT were observed during the study. The highest levels of TT and CFT were observed 1-2 weeks after each injection and the lowest immediately before the second injection. • Insufficient levels of TT (< 8 nmol/L) were observed in 10 patients, with nine of these during the second half of the first treatment cycle. Supernormal levels of TT (> 35 nmol/L) were measured in 28 patients of which 26 occurred at least once during the first 3 weeks of each treatment cycle. • A follow-up review at median 39 months after study start showed a median steady-state injection interval of 10 weeks, with an individual variability of 6-14 weeks. Symptoms according to the Aging Males' Symptoms scale remained unchanged. No severe toxicity was encountered. Only one patient experienced transient elevation of serum alanine transaminase and aspartate transaminase with maximal Common Toxicity Criteria, grade 2. CONCLUSIONS: • TU is safe and highly efficient for the treatment of anorchid GCTC survivors. • Androgen substitution with TU in bilateral GCTC survivors requires individually-adjusted injection intervals. In most cases, 10-week intervals appear to be sufficient.

Is psychological distress in men recently diagnosed with testicular cancer associated with their neuropsychological test performance?

OBJECTIVE: To study the level of cancer-related distress (CRD) and variables associated with CRD in recently diagnosed testicular cancer patients (TCPs), and to explore associations between distress levels and neuropsychological test performance at the same time-point. METHODS: As part of a prospective study of their psychological and cognitive functioning, 135 TCPs completed the Impact of Event Scale (IES) as a measure of CRD at a median of 37 days after diagnosis. They also completed the Hospital Anxiety and Depression Scale (HADS) and the Positive and Negative Affect Schedule (PANAS). Among 135 TCPs, 131 were interviewed and 129 were also tested with a neuropsychological battery. All investigations were done after orchidectomy but before any additional treatment. The associations between neuropsychological test-scores and IES, HADS and PANAS were examined. RESULTS: Twenty-four percent (95%CI 17%-31%) of the TCPs reported clinically significant CRD (IES-total score>26). No demographic or cancer-related variables were associated with the CRD-level. In univariate analyses, previous mental problems, sleeping problems, a higher level of neuroticism, daily smoking and hazardous alcohol-use were significantly associated with the CRD-level. In multivariate analysis neuroticism, smoking and alcohol-use remained significantly associated with CRD. Four out of 18 neuropsychological test-scores were significantly associated with at least one distress-measure. Increasing distress-levels were associated with decreasing test performance on some measures of attention, working memory and executive functions. CONCLUSIONS: In newly diagnosed TCPs, the scores on neuropsychological tests should be considered in relation to co-existing mental distress. Future studies should consider adjustment for this on relevant tests.

[Testicular cancer]. / Testikkelkreft.

BACKGROUND: Testicular cancer is the most common type of cancer among Norwegian 15 to 40-year-old men. The incidence has doubled in Norway and Denmark during the last 50 years and is currently the highest in the world. MATERIAL AND METHODS: The review article is based on relevant publications, own research and clinical experience. RESULTS AND INTERPRETATION: Post-orchiectomy treatment is only offered at university hospitals. Cisplatin-based chemotherapy (introduced in Norway in the early 1980s) has resulted in a remarkably improved survival for patients with advanced testicular cancer. Most patients are cured (> 80%), also those with metastases. Cancer-related survival approaches 95%. Treatment-induced side effects and efforts to reduce these have been an issue of increasing importance during recent years.

[Anticancer drug dosing--pharmacogenomic biomarkers or body surface area?]. / Cytostatikadosering etter farmakogenomiske markører eller kroppsoverflate?

BACKGROUND: Chemotherapeutic treatment regimes are established for most cancer forms. In general, these substances have extremely narrow therapeutic windows, which render cancer patients vulnerable to over- and underdosing. Individual drug dosing is currently based on the patients' body surface area. This practice is an extrapolation from animal studies. Recent advances in molecular medicine raise the question of whether the present dosing strategy should be adjusted to individual functional DNA variants affecting the metabolism, transport and efficacy of anticancer drugs. MATERIAL AND METHODS: This review is based on selected references retrieved from PubMed and the authors' experience in drug treatment of cancer patients. RESULTS: Several single nucleotide polymorphisms and other DNA variants that contribute to varying clinical response to chemotherapeutic agents were identified. For some drugs it has been shown that unfavourable DNA variants can lead to life-threatening side effects and/or suboptimal treatment. INTERPRETATION: There is a compelling need for prospective, randomized studies to establish the prognostic values of pharmacogenomic markers. With few exceptions the current knowledge is insufficient to include genotype analyses in routine planning of anticancer drug treatment. In most clinical situations, individual drug dosing according to body surface area in addition to therapeutic drug monitoring and close clinical surveillance is still the preferred approach to treat cancer patients.

Influence of everolimus on steady-state pharmacokinetics of cyclosporine in maintenance renal transplant patients.

To investigate possible interactions of the novel immunosuppressant everolimus with cyclosporine, a multicenter, randomized, double-blind, placebo-controlled, dose-escalating phase I study was performed. Everolimus regimens (0.75-10 mg/d) were administered for 28 days to stable renal allograft recipients receiving the microemulsion form of cyclosporine. Steady-state cyclosporine profiles were assessed at baseline on day 0 (cyclosporine alone) and on day 21 with everolimus on steady state. By day 21, mean dose-normalized cyclosporine AUC0-12 increased by 15% in patients receiving placebo. In everolimus-treated patients, mean increases in cyclosporine AUC0-12 ranged from 7% to 43%, which were not significantly different across all dosing cohorts including placebo. Linear regression of everolimus AUC on day 21 versus the increase in cyclosporine AUC0-12 yielded a slope not significantly different from a horizontal line (P = ns). In conclusion, these results suggest that steady-state everolimus exposure over the wide range assessed in this study did not affect steady-state cyclosporine pharmacokinetics.

Exome sequencing of bilateral testicular germ cell tumors suggests independent development lineages.

Intratubular germ cell neoplasia, the precursor of testicular germ cell tumors (TGCTs), is hypothesized to arise during embryogenesis from developmentally arrested primordial germ cells (PGCs) or gonocytes. In early embryonal life, the PGCs migrate from the yolk sac to the dorsal body wall where the cell population separates before colonizing the genital ridges. However, whether the malignant transformation takes place before or after this separation is controversial. We have explored the somatic exome-wide mutational spectra of bilateral TGCT to provide novel insight into the in utero critical time frame of malignant transformation and TGCT pathogenesis. Exome sequencing was performed in five patients with bilateral TGCT (eight tumors), of these three patients in whom both tumors were available (six tumors) and two patients each with only one available tumor (two tumors). Selected loci were explored by Sanger sequencing in 71 patients with bilateral TGCT. From the exome-wide mutational spectra, no identical mutations in any of the three bilateral tumor pairs were identified. Exome sequencing of all eight tumors revealed 87 somatic non-synonymous mutations (median 10 per tumor; range 5-21), some in already known cancer genes such as CIITA, NEB, platelet-derived growth factor receptor α (PDGFRA), and WHSC1. SUPT6H was found recurrently mutated in two tumors. We suggest independent development lineages of bilateral TGCT. Thus, malignant transformation into intratubular germ cell neoplasia is likely to occur after the migration of PGCs. We reveal possible drivers of TGCT pathogenesis, such as mutated PDGFRA, potentially with therapeutic implications for TGCT patients.

Pharmacokinetics of diltiazem and its metabolites in relation to CYP2D6 genotype.

OBJECTIVES: Recently, it was shown in vitro that the polymorphic enzyme cytochrome P450 (CYP) 2D6 mediates O-demethylation of diltiazem. The aim of this study was to compare the pharmacokinetics of diltiazem and its major metabolites in healthy human volunteers representing different CYP2D6 genotypes. METHODS: Norwegians of Caucasian origin were screened for their CYP2D6 genotype on the LightCycler (Roche Diagnostics, Mannheim, Germany) by melting-curve analysis of allele-specific fluorescence resonance energy transfer probes hybridized to polymerase chain reaction-amplified deoxyribonucleic acid. The first 5 individuals identified with genotypes corresponding to a homozygous extensive, heterozygous extensive, or homozygous poor CYP2D6-metabolizing phenotype, respectively, were voluntarily enrolled in the pharmacokinetic study. The participants received diltiazem, 120 mg, as a single oral dose, and plasma samples were collected up to 24 hours after administration. Plasma samples were purified by solid phase extraction. Diltiazem and 7 phase I metabolites were analyzed by liquid chromatography-mass spectrometry. RESULTS: The pharmacokinetics of diltiazem was not significantly different between the subgroups. However, the systemic exposure of the pharmacologically active metabolites desacetyl diltiazem and N-demethyldesacetyl diltiazem was > or = 5 times higher in poor CYP2D6 metabolizers than in extensive CYP2D6 metabolizers (P <.01). CONCLUSIONS: CYP2D6 activity does not have a major impact on the disposition of diltiazem. In contrast, desacetyl diltiazem and N-demethyldesacetyl diltiazem are markedly accumulated in individuals expressing a deficient CYP2D6 phenotype. Because these metabolites exhibit pharmacologic properties of possible importance, individual CYP2D6 activity might be an aspect to consider in the clinical use of diltiazem.

Probability of metachronous testicular cancer in patients with biopsy-proven intratubular germ cell neoplasia depends on first-time treatment of germ cell cancer.

PURPOSE: To evaluate the probability of subsequent testicular cancer (STC) in patients with intratubular germ cell neoplasia unclassified (IGCNU) treated for first-time invasive germ cell cancer. PATIENTS AND METHODS: Sixty-one patients with germ cell testicular cancer or extragonadal germ cell cancer received follow-up from diagnosis of IGCNU to development of STC, initiation of IGCNU-definitive treatment (orchiectomy/radiotherapy), emigration, death, or end of follow-up. The probability of STC was assessed in subgroups according to chemotherapy burden. RESULTS: The probability of STC in the nonexposed patients was significantly increased compared with those exposed to chemotherapy (P = .05; 5-year probability of 54% [95% CI, 33% to 78%] and 23% [95% CI, 11% to 45%], respectively). In the group of patients treated with one to three cycles or no chemotherapy, the probability of STC was significantly increased compared with those exposed to four or more cycles (P = .03; 5-year probability of 42% [95% CI, 27% to 62%] and 22% [95% CI, 8% to 54%], respectively). Twenty-two of 22 patients were tumor-free and alive at a median of 56 months (range, 2 to 184 months) after diagnosis of STC. CONCLUSION: Platinum-based chemotherapy may reduce the probability of STC in patients with IGCNU, particularly in those treated with four or more cycles of chemotherapy. A watch-and-wait strategy for patients with IGCNU may be justified in selected patients with future plans for paternity.

Self-reported cognitive problems in testicular cancer patients: relation to neuropsychological performance, fatigue, and psychological distress.

OBJECTIVE: There is a concern about negative cognitive effects of systemic chemotherapy. We prospectively explored self-reported cognitive problems in testicular cancer patients (TCPs) treated with and without chemotherapy. METHODS: One hundred and twenty-two TCPs were interviewed about concentration and memory problems shortly after orchidectomy but before any additional treatment (baseline), and then at a median of 1 year after end of treatment (follow-up). Symptoms of psychological distress, fatigue, and peripheral neurotoxicity were assessed by questionnaires, and patients also underwent neuropsychological testing. Self-reported cognitive problems were compared between three treatments groups: no chemotherapy, one cycle of chemotherapy, and multiple cycles of chemotherapy. Variables associated with an increase of self-reported cognitive problems from baseline to follow-up were explored. RESULTS: Significantly larger proportions of TCPs in the two chemotherapy groups had an increase of self-reported cognitive problems from baseline to follow-up compared to the no-chemotherapy group. Increase of self-reported cognitive problems was significantly associated with psychological distress, fatigue, lower level of education, and Raynaud-like symptoms, but not with a decline in neuropsychological test performance. CONCLUSION: In this explorative study of TCPs, an increase of self-reported cognitive problems from baseline to 1-year follow-up was associated with chemotherapy and with symptoms of fatigue and psychological distress at follow-up, while no significant association was found with a decline in neuropsychological test performance.

Upregulation of stem cell genes in multidrug resistant K562 leukemia cells.

The transmembrane transporter P-glycoprotein (P-gp) encoded by ABCB1, is one major cause for multidrug resistance (MDR). We compared the genomic profile and gene expression pattern of the P-gp positive K562VCR cells with parental P-gp negative K562wt cells. In K562VCR array CGH revealed amplification of ABCB1, ABCB4, ABCB5 and SEMA3D, whereas expression microarrays demonstrated upregulation of stem cell genes (e.g. KIT and HOXB4), anti-apoptotic genes (e.g. IGF1R and CCNG1), and downregulation of pro-apoptotic genes (e.g. CASP4, 6 and 7). Thus, K562VCR cells disclose stem cell characteristics including a range of drug resistance mechanisms possibly attained as a stem cell program switched on en bloc.

Influence of ceramide metabolism on P-glycoprotein function in immature acute myeloid leukemia KG1a cells.

Previous studies have emphasized the role of glucosylceramide (Glu-Cer) synthase in multidrug resistance (MDR) regulation. However, the mechanism by which the inhibition of this enzyme results in increased drug retention and cytotoxicity remains unclear. In this study, we investigated the respective role of ceramide (Cer) accumulation and Glu-Cer derivatives depletion in MDR reversal effect of 1-phenyl-2-decanoylamino-3-morpholino-1-propanolol (PDMP), a Glu-Cer synthase inhibitor. We show here that treatment with PDMP resulted in increased rhodamine 123 (Rh123) retention and potent chemosensitization of P-glycoprotein (P-gp)-expressing cells, including KG1a cells, KG1a/200 cells, K562/138 cells, and K562/mdr-1 cells. Metabolic studies revealed that PDMP induced not only time-dependent Cer accumulation but also reduction of all glycosylated forms of Cer, including Glu-Cer, lactosylceramide (Lac-Cer), monosialo ganglioside (GM3) and disialo ganglioside (GD3). The influence of these metabolites on P-gp function was investigated by measuring Rh123 retention in PDMP-treated cells. P-gp function was found to be stimulated only by the addition of gangliosides in all resistant cell lines, whereas Glu-Cer, Lac-Cer, and Cer had no effect. Moreover, in KG1a/200 cells, GD3 and, to a lesser extent, GM3 were found to phosphorylate P-gp on serine residues. Altogether, these results suggest that, at least in leukemic cells, gangliosides depletion accounts for PDMP-mediated MDR reversal effect, and that gangliosides are important P-gp regulators perhaps through their capacity to modulate P-gp phosphorylation.

Tolerability and steady-state pharmacokinetics of everolimus in maintenance renal transplant patients.

BACKGROUND: Current immunosuppressant regimens need to be improved to prevent acute and chronic graft rejection. The novel macrocyclic immunosuppressant everolimus (Certican, RAD) is currently in clinical development to address this issue. METHODS: The primary objective of this multicentre, randomized, double-blind, placebo-controlled, dose-escalating phase 1 study was to evaluate the safety and tolerability of everolimus at four dose levels (0.75, 2.5, 5 and 10 mg/day) in maintenance renal transplant patients receiving cyclosporin and steroids. The secondary objective was to assess the pharmacokinetic profile of two different formulations (capsule and tablet) of everolimus. RESULTS: Fifty-four subjects were randomized for 4 weeks treatment with everolimus (n = 44) or placebo (n = 10). Dose levels of everolimus between 0.75 and 5 mg daily were well tolerated, permitting dose escalation to the highest everolimus dose of 10 mg daily. At this dose, everolimus was associated with a higher incidence and severity of adverse events, most notably thrombocytopenia. Pharmacodynamic assessment showed a relationship between drug exposure and thrombocytopenia. Notable reversible elevations of cholesterol were also observed at the 10 mg/day dose. Other changes in laboratory evaluations, including triglycerides, were minor, reversible and did not appear to be dose dependent. The bioavailability of the tablet formulation was 2.6-fold higher compared with the capsule, with evidence for dose proportionality over the dose range tested. Within-subject pharmacokinetic variability was low (coefficient of variation: 10-19%); however, between-subject variability ranged from 34 to 60% for AUC and C(max). CONCLUSIONS: These results indicate that up to 5 mg/day everolimus results in a dose-proportional exposure, and is adequately well tolerated in renal transplant recipients receiving cyclosporin and steroids.