Gustav Lehne

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.

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.

The cyclosporin PSC 833 increases survival and delays engraftment of human multidrug-resistant leukemia cells in xenotransplanted NOD-SCID mice

Circumvention of chemoresistance in cancer may involve several modulator drugs with high affinity for the multidrug transporter P-glycoprotein (Pgp), which is expressed in a number of multi-resistant malignancies. Pgp acts as a membrane efflux pump with broad substrate specificity including antineoplastic drugs and endogenous substances such as certain cytokines and sphingolipids. Therefore, the consequence of Pgp blockade could be far more complex than intracellular drug retention. In the present study exposure of the Pgp inhibitor, PSC 833 (1200 ng/ml), to Pgp expressing KG1a/200 human leukemia cells provoked cell cycle arrest and apoptosis in vitro. This finding was put to test in vivo using a xenotransplant model of KG1a/200 human cells intravenously inoculated into non-obese diabetic severe combined immunodeficient (NOD-SCID) mice. The animals were randomly allocated to receive treatment with PSC 833 (n = 32) or placebo (n = 24). PSC 833 (30 mg/kg) was subcutaneously injected six or 12 times separated by 48–96 h. The overall mean whole blood concentration of PSC 833 was 1191 ± 60 ng/ml (s.e.m.) at 20 h after administration. Tumor engraftment was significantly reduced in the treatment group (P = 0.037), which also had prolonged survival compared to control animals (P = 0.0016). This is the first study that demonstrates antileukemic effects of a Pgp inhibitor as single agent therapy in vivo, and the present data raise the possibility of alternative exploitation of modulators in cancer chemotherapy.

A prospective study of neuropsychological functioning in testicular cancer patients

BACKGROUND Whether systemic chemotherapy has a negative effect on cognitive function in patients, concern oncologists. In testicular cancer patients (TCPs) treated with cisplatin-based chemotherapy, only few cross-sectional studies have addressed this concern. We prospectively studied neuropsychological functioning in TCPs. PATIENTS AND METHODS In a consecutive sampling, 122 TCPs were examined at baseline (after orchidectomy, before any additional treatment) and then at follow-up at a median of 12 months after end of treatment. The examinations included a neuropsychological test battery, interview on background variables and questionnaires on mental distress, fatigue and neurotoxic symptoms. Changes in neuropsychological functioning from baseline to follow-up were compared between three treatments groups: no chemotherapy (N = 31), one cycle of chemotherapy (N = 38) and two or more cycles of chemotherapy (N = 53). Variables associated with a decline in neuropsychological test performance from baseline to follow-up were explored. RESULTS No statistically significant differences in proportions of TCPs with a decline in neuropsychological test performance were observed between the three treatment groups. Decline in neuropsychological test performance was not associated with demographic variables, distress, fatigue or with chemotherapy. CONCLUSION No negative effect of systemic chemotherapy on neuropsychological test performance in TCPs at 1-year follow-up was found in this study.

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.

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.

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.

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

Study Type – Therapy (case series)
 Level of Evidence 4