Bernd Flath

Biomarkers of depression in cancer patients

Inflammation and perturbation of the hypothalamic‐pituitary‐adrenal (HPA) axis function appears to play a putative role in the etiology of depression. Patients with metastatic cancer demonstrate elevated prevalence rates for depression. The objective of the current study was to illustrate the efficacy of interleukin‐6 (IL‐6) and HPA axis function as adjuncts to support the diagnosis of depression in cancer patients.

PHASE II TRIAL OF GEMCITABINE AS PROLONGED INFUSION IN METASTATIC BREAST CANCER

Gemcitabine is an active agent in the treatment of metastatic breast cancer. The phosphorylation of gemcitabine into the active gemcitabine triphosphate (dFdCTP) is catalyzed by deoxycytidine kinase. This enzyme is saturated at plasma concentrations achieved after an infusion over 30 min. Therefore

Prolonged infusion of gemcitabine in stage IV breast cancer: a phase I study.

Gemcitabine is an effective agent in the treatment of metastatic breast cancer. The phosphorylation of gemcitabine into the active gemcitabine triphosphate (dFdCTP) is catalyzed by deoxycytidine kinase. This enzyme is saturated at plasma concentrations achieved after an infusion over 30 min. Therefore accumulation of higher intracellular dFdCTP concentrations, which may result in an enhanced antineoplastic activity, cannot be achieved by higher dosage, but only by prolonged infusion time. The objectives of this phase I trial were to determine the dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD) of gemcitabine given as a 6 h i.v. infusion. Patients with metastatic breast cancer were treated with gemcitabine as a 6 h infusion on days 1, 8 and 15 every 4 weeks. The starting dose was 200 mg/m2 with an interindividual escalation in 50 mg/m2 increments. Sixteen patients received 196 doses through three dose levels. All patients were assessable for toxicity, 13 assessable for response. The MTD was 250 mg/m2. DLT was observed at 300 mg/m2 consisting of a reversible elevation of transaminases WHO grade 3 in two patients and cutaneous toxicity grade 3 in one patient. Most common non-hematologic toxicities were mild to moderate and rapidly reversible elevation of liver enzymes in all patients, nausea and vomiting (four patients grade 2, five patients grade 3), and mild alopecia. Hematologic toxicity was mild with neutropenia WHO grade 3 and 4 in only one patient each, and no grade 3 thrombocytopenia. One patient achieved a complete remission and another patient a partial response, for an overall response rate of 15% (two of 13). In addition, seven patients (54%) had stable disease and four (31%) failed to respond to the treatment. We conclude gemcitabine 250 mg/m2 days 1, 8 and 15 every 4 weeks can be safely administered as 6 h infusion. Toxicity, especially myelosuppression, is surprisingly mild. Based on this result a phase II study with 250 mg/m2 administered over 6 h was initiated to determine the efficacy.

Association of IL-6, Hypothalamus- Pituitary-Adrenal Axis Function, and Depression in Patients With Cancer

Background: Evidence suggests that cytokines (IL-6) and alteration of the hypothalamic—pituitary—adrenal (HPA) axis play a crucial role in the etiology of depression. Patients with cancer show elevated prevalence rates for depression. The objective of this cross-sectional study was to investigate the associations between these abnormalities and depression. Methods: Plasma concentrations of IL-6 and cortisol were measured in cancer patients with (N = 31) and without depression (N = 83). The relative diurnal variation of cortisol (cortisol VAR), expressed in percentage, was calculated. Results: There was a significant difference in median plasma concentration of IL-6 between the patients with depression and those without (18.7 vs 2.7 pg/mL; P < .001). Relative cortisol VAR was decreased in depressed patients as compared with patients without depression (11.72% vs 60.6%, P = .037). A positive correlation between the depressive symptoms and IL-6 concentration was found (r = 0.469, P < .001). Negative correlations were found between cortisol VAR versus depressive symptoms and cortisol VAR versus IL-6 (r = -0.6, P < .001 and r = -0.52, P < .001, respectively). IL-6 (odds ratio [OR] = 1.1; 95% confidence interval [CI] = 1.0-1.2; P = .006) and cortisol VAR (OR = 1.3; 95%CI = 1.0-1.4; P = .02) are independently associated with depression. Conclusions: Depression in cancer is associated with increased plasma IL-6 concentrations and dysfunction of the HPA axis.

Breast Cancer-Associated Thrombotic Microangiopathy

Background: Thrombotic microangiopathy (TMA) is defined as thrombocytopenia and microangiopathic hemolytic anemia. Cancer-associated TMA, a rare but fatal condition, seems an entity distinct from classical thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS). Patients and Methods: All patients with breast cancer-associated TMA treated at our institution between 2003 and 2008 were analyzed retrospectively. To elucidate pathophysiological mechanisms, we measured the serum activity of the metalloprotease ADAMTS13. Results: 8 patients were identified. All showed bone marrow infiltration of breast cancer as well as thrombocytopenia, schistocytes, and hemolytic anemia. ADAMTS13 activity was mildly decreased in 4/6 patients (20–108%, normal range 30–120%), but none showed severely low levels as is characteristic of classical TTP. 6 patients were treated with anthracycline-containing fractionated chemotherapy, 5/6 patients experienced partial response. Overall survival was 13 months. Fractionated chemotherapy was well tolerated. Conclusions: Cancer-associated TMA has an underlying mechanism different from classical TTP. While bone marrow infiltration might be of major relevance, ADAMTS13 deficiency seems to be an epiphenomenon. Fractionated chemotherapy resulted in higher remission rates and comparatively long survival.

Anti‐Ta‐associated paraneoplastic encephalitis with occult testicular intratubular germ‐cell neoplasia

Anti-Ta-associated encephalitis is a paraneoplastic inflammatory brain disorder with immune-mediated neurological symptoms. The well-characterised onconeuronal antibody, anti-Ta, reacts with the paraneoplastic protein PNMA2 (former antibody name: anti-Ma2). 1 Neurological symptoms often include abnormalities in eye movement, short-term memory loss, seizures, irritability, personality change or confusion.2,3 The symptoms tend to precede tumour diagnosis and are often more debilitating than the malignancy itself.2 The first study of anti-Ta-related paraneoplastic encephalitis reported 10 young men with testicular cancer.3 Other tumours occur in females4 and approximately 30 cases have been reported.2,5 Several tumours express the protein that, in healthy adults, is restricted to brain and testicular germ cells.3 In contrast to other paraneoplastic syndromes, a remarkable number of patients show neurological improvement if the underlying tumour allows complete surgical resection.2 We report a patient’s history of anti-Ta-associated neurological syndrome with atypical parkinsonism and massive rigidity due to occult testicular cancer. In 2001, a 66-year-old man suddenly developed disorientation, restlessness, psychomotor agitation and fever. A bradykinetic syndrome with rigidity was noted. Verbal output was reduced and the patient responded only in short sentences. Head CT and lumbar puncture examinations were normal, and EEG demonstrated a right temporal epileptic focus. After 2 weeks, the patient was admitted to the Department of Neurology, Charite, University Medicine Berlin, Berlin, Germany, with further neurological deterioration. He was drowsy, with markedly reduced verbal output, and only occasionally followed simple …

Multi-omic based molecular profiling of advanced cancer identifies treatable targets and improves survival in individual patients

A proof-of-concept study was conducted to assess whether patients with advanced stage IV cancer for whom predominantly no standard therapy was available could benefit from comprehensive molecular profiling of their tumor tissue to provide targeted therapy. Tumor samples of 83 patients were collected under highly standardized conditions and analyzed using immunohistochemistry, next-generation sequencing and phosphoprotein profiling. Expression and phosphorylation of key oncogenic pathways were measured to identify targets at the (phospho-) proteomic level. At genomic level, 50 oncogenes and tumor suppressor genes were analyzed. Based on molecular profiling, targeted therapies were decided by the attending oncologist. Accordingly, 28 patients who met the defined criteria fell in two equal-sized groups. One group received targeted therapies while the other did not. Following six months of treatment, disease control was achieved by 49% of patients receiving targeted therapy (complete remission, 14%; partial remission, 21%; stable disease, 14%; disease progression, 36%; death, 14%) and 21% of patients receiving non-targeted therapy (stable disease, 21%; disease progression, 64%; death, 14%). Individual patients experienced dramatic responses to a therapy which otherwise would not have been applied. This approach clarifies the value of multi-omic molecular profiling for cancer diagnostics.

Paradigmenwechsel hin zu einer chronischen Behandlung

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Exulzeriertes, blutendes Mammakarzinom: seltene Ursache einer Eisenmangelanämie beim Mann

E 63 Jahre alter Mann aus Bosnien stellte sich wegen zunehmender körperlicher Schwäche und Luftnot vor. Beifällig erwähnte er, dass er seit etwa 2 Jahren eine zunehmende, wiederholt blutende „Schwellung“ der linken Brust bemerkte. Bei der körperlichen Untersuchung zeigte sich ein etwa 15 cm großer, exulzerierter Mammatumor mit kleinen Sickerblutungen (Abbildung 1). Beidseits axillär waren mit der Umgebung verbackene Lymphknoten mit einer maximalen Größe von etwa 3 cm tastbar. Der Blutdruck lag bei 100/60 mmHg, die Herzfrequenz bei 90/min. In den Laboruntersuchungen fiel eine Eisenmangelanämie (Hb 9,1 g/dl) auf. Mittels Computertomographie des Thorax wurden eine komplette Infiltration der linksseitigen Thoraxwand (Abbildung 2) und mehrere Lungenmetastasen nachgewiesen. Die histologische Diagnose lautete invasives duktales Karzinom (Proliferationsfraktion 20%, Östrogenund Progesteronrezeptoren positiv, Überexpression von c-erbB2). Aufgrund des fortgeschrittenen Tumorleidens war eine chirurgische Intervention nicht möglich. Die Indikation für eine Bestrahlung musste wegen der Gefahr einer ausgeprägten Nekrotisierung mit nachfolgender Superinfektion zurückhaltend gestellt werden. Es wurde eine Chemotherapie nach dem TAC-Protokoll [1] mit Docetaxel, Doxorubicin und Cyclophosphamid eingeleitet. Hierunter kam es nach drei Zyklen zu einer partiellen Remission. Das Mammakarzinom des Mannes ist eine seltene Erkrankung. Es macht nur etwa 1% aller Mammakarzinome und 0,2–0,5% der Karzinome beim Mann aus. In einigen afrikanischen Staaten, insbesondere in Ägypten, liegt die Häufigkeit dagegen bei 5–15% der Karzinome des Mannes [2]. Die Tumorinzidenz liegt bei etwa 0,6 Fällen pro 100 000 Einwohner. Sie nimmt im fortgeschrittenen Lebensalter zu (0,1 Fälle pro 100 000 Einwohner im Alter von 30–34 Jahren; 6,5 Fälle pro 100 000 Einwohner bei Männern > 85 Jahre) und ist in Europa am höchsten in Frankreich, Ungarn, Österreich, Schottland und Portugal. Der Altersgipfel liegt mit 60 Jahren ca. 10 Jahre höher als bei der Frau [2]. 1 Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie, Universitätsklinikum Charité (Campus Mitte) der Humboldt-Universität zu Berlin.