Influence of age, performance status, cancer activity, and IL-6 on anxiety and depression in patients with metastatic breast cancer.

Depression and anxiety are the core disorders causing emotional distress in patients (pts) with metastatic breast cancer. The aim of our study was to screen metastatic breast cancer outpatients for anxiety and depression, and to investigate the influence of age, Karnofsky Performance Status (KPS), cancer activity, and inflammation as represented by IL-6 levels on these two mood disorders. Pts treated with chemotherapy for metastatic breast cancer (n = 70) were assessed using the Hospital Anxiety and Depression Scale (HADS) for symptoms (scores 0-21) and caseness (score ≥11) of clinical depression and anxiety. Blood samples for IL-6 concentrations were collected at 10:00 a.m. A total of 22 (31.4 %) pts were diagnosed with caseness of clinical depression and 23 (32.9 %) pts with clinical anxiety, while 12 pts were diagnosed positive for both mood disorders. Depression and anxiety were positively but moderately correlated (Spearman's r (2) = 0.24, p < 0.001). IL-6 was significantly correlated with symptoms of depression (r (2) = 0.42, p < 0.001) and to a lesser extent to symptoms of anxiety (r (2) = 0.16, p = 0.001). In addition, IL-6 was positively associated with tumor progression (p < 0.001). Multiple linear regression analysis showed that tumor progression (standardized b = 0.226, p = 0.047), symptoms of anxiety (b = 0.292, p = 0.016), and IL-6 (b = 0.314, p = 0.007) were independently associated with clinical depression, whereas anxiety was linked to tumor progression (b = 0.238, p = 0.030), symptoms of depression (b = 0.407, p < 0.001) and age (b = -0.381, p < 0.001), but not to IL-6 (b = 0.168, p = 0.134). Even though a positive correlation between depression and anxiety exists, clinical parameters like age, cancer activity, KPS, and IL-6 do influence depression and anxiety differently. Unlike clinical depression, anxiety is not associated with increased IL-6 levels, however, shows a reciprocal correlation with age.

Neurocognitive function, brain-derived neurotrophic factor (BDNF) and IL-6 levels in cancer patients with depression.

BACKGROUND: Increased IL-6 and decreased brain-derived neurotrophic factor (BDNF) levels have been implicated in the pathophysiology of depression. The objective was to assess the influence of BDNF and IL-6 on cognitive function and depression in patients with cancer. METHODS: Serum BDNF and plasma IL-6 were measured in patients with metastatic cancer. Diagnosis of depression was established according to DSM-IV criteria. Cognitive function was assessed by the Verbal Learning and Memory Test (VLMT). RESULTS: A total of 59 patients were recruited in this study. Only IL-6 levels were significantly elevated in patients with clinical depression (35.7 vs. 6.9 pg/ml; p<0.001). There were no differences in hemoglobin levels (p=0.3) or BDNF levels (p=0.16). Patients with clinical depression showed significant impairment of short-term memory (STM) (24.4 vs. 37.5; p=0.01), but not of long-term memory (LTM) (3.9 vs. 2.8; p=0.3). STM was dependent on the level of BDNF and younger age (b=0.60; p=0.001; b= -0.63; p=0.003, respectively). IL-6 was not only strongly associated with depression, but was an independent predictor of BDNF level as well (b= -0.50; p=0.01). LTM was associated only with a good KPS (b=0.47; p=0.037). Hemoglobin levels and the prior number of chemotherapy lines were not predictive of memory performance. CONCLUSIONS: Low BDNF is associated with cognitive impairment, STM, in patients with cancer, however no influence on depression could be found. IL-6 is strongly associated with depression and an independent predictor of BDNF levels.

Lonidamine in high-risk breast cancer patients.

Lonidamine revealed synergistic effects with anthracyclines and alkylating agents in experimental investigations. It differs from conventional cytostatics by acting on the cell energy metabolism and also lacks their typical side effects; therefore it may be valuable to be combined with established chemotherapeutic regimens. Because in unselected patients the results of randomized studies may be influenced by differences in type and combination of prognostic factors, we defined strict entry criteria: no previous systemic palliative treatment, disease-free interval less than or equal to 2 years, measurable visceral metastases, number of tumor sites less than or equal to 2, no brain or bone metastases, World Health Organization performance status less than or equal to 2, age less than or equal to 55. In an ongoing rate, remission duration, time to treatment failure, and survival time in patients treated with vindesin 3 mg/m2 plus epirubicin 100 mg/m2 plus cyclophosphamide 600 mg/m2 (day 1, intravenous, repeated every 3 weeks) +/- lonidamine 600 mg/day orally. Eight of 12 patients achieved an objective remission (complete response 4, partial response 4), 1 patients had a stable disease, 2 patients experienced tumor progression; 1 patient is not yet evaluable for response. In spite of the intensity of the therapy no treatment interval prolongation was necessary. Main toxicities were myelosuppression, nausea, emesis, alopecia, and in patients treated with lonidamine, mild myalgia. The addition of lonidamine to polychemotherapy did not affect myelosuppression. Differences in remission rates or remission duration due to lonidamine could not yet be demonstrated.

Gemcitabine for palliative treatment in metastatic breast cancer.

Gemcitabine is one of the recently developed drugs with a high efficacy in various malignant tumours and a mild toxicity profile. As monochemotherapy in metastatic breast cancer, gemcitabine yielded response rates up to 46% as first- and second-line treatment. Neutropenia is the clinically most relevant unwanted effect. Haematological and nonhaematological toxicities are mild, making dose reductions, delays of treatment or withdrawal from treatment very rare. The first phase I and phase II studies of gemcitabine in combination with anthracyclines have shown a good toxicity profile and promising remission rates. Phase I experiences with long-time infusion schedules reveal good feasibility and high patient acceptance.

Orbital metastases in breast cancer: report of two cases and review of the literature.

PURPOSE: Intraorbital metastases of solid tumors are a rarely diagnosed clinical condition, even though pathological reports suggest an incidence of up to 30% in cancer patients. We report two cases of intraorbital, extraocular metastases in breast cancer. The first patient was a 45-year-old man who presented with diplopia, upward divergence of the left bulb, and local pain. METHODS: In the standard cerebral magnetic resonance imaging (MRI) no cerebral or ocular tumor was detectable. A subsequent T1-weighted, contrast-enhanced orbital MRI with fat suppression revealed an infrabulbar mass of 18 x 13 mm in size. The second patient, a 59-year-old woman, complained of slight diplopia when looking to the left. Cerebral MRI with fat suppression showed a retrobulbar mass with 17x13 mm. In both patients metastatic breast cancer was known for several years, and both had been in a stable disease situation. Both patients were treated with stereotactic radiation, applying a cumulative dose of 35 and 45 Gy, respectively, which resulted in marked improvement of local symptoms. Most eye metastases of breast cancer are located in the choroidea, while an extrabulbar localization within the orbit is rare, with only 3-10% of all ocular metastases. Autopsy reports reveal that an estimated 10-30% of breast cancer patients develop this form of metastasis. This is in strong contrast to rare clinical case reports, suggesting frequently absent to mild clinical signs and difficult diagnosis. CONCLUSION: If breast cancer patients complain of ophthalmological symptoms such as local pain, impaired vision, or diplopia, it is important to consider ocular or orbital metastatic disease.

Immunohistochemical detection of CD5 with monoclonal antibody 4C7 on paraffin sections.

CD5 is useful for the classification of low-grade B-cell lymphomas, because it is aberrantly expressed in B-cell chronic lymphocytic leukemias/small lymphocytic lymphomas (B-CLLs/SLLs) and mantle cell lymphomas (MCLs), but not in the other well-described low-grade B-cell lymphomas. Therefore, we tested the utility of monoclonal antibody (MAb) 4C7 to detect CD5 on paraffin sections of 22 cases with low-grade B-cell lymphomas and 4 cases with high-grade B-cell lymphomas and compared the results with CD5 detection by analysis of fresh tissue with a fluorescent-activated cell sorting (FACS). After heat-induced epitope retrieval we could detect CD5 on paraffin sections in all MCLs and B-CLLs/SLLs, identical to the results of flow cytometry. Eleven of 12 cases that showed no CD5 expression by FACS analysis were also negative on paraffin sections. In only one case of a presumed blastoid MCL, CD5 was detectable by immunohistochemistry but not by FACS analysis. We conclude that MAb 4C7 against CD5 is a useful paraffin-reactive marker, especially to correctly identify MCLs on paraffin sections.

Immunohistochemical detection of CD10 with monoclonal antibody 56C6 on paraffin sections.

We tested a total of 174 paraffin-embedded hematolymphoid neoplasias to determine whether CD10 can be specifically and sensitivity detected on paraffin sections using monoclonal antibody 56C6 after epitope retrieval. For 32 cases, results of CD10 detection by immunohistochemistry were compared with flow cytometric data. In only 1 case of follicle center lymphoma, divergent staining results were found with the detection of CD10 by flow cytometry but not by immunohistochemistry. Altogether, 22 of 28 follicle center lymphomas, 2 of 6 hairy cell leukemias, 14 of 34 diffuse large B-cell lymphomas, 3 of 3 Burkitt lymphomas, 4 of 5 precursor B-lineage acute lymphoblastic leukemias, and 2 of 4 T-lymphoblastic lymphomas were CD10+. Decalcification of bone marrow biopsy specimens did not diminish the staining intensity. All other cases, including 10 acute myeloid leukemias and a range of low-grade B-cell lymphomas, were CD10-. CD10 is reliably detectable with antibody 56C6 on paraffin sections using epitope retrieval. The antibody is especially useful for the subclassification of acute leukemias and low-grade B-cell lymphomas.

Mixed infection of human U-937 cells by two different species of Leishmania.

Mixed infections by different Leishmania species could explain differences in the clinical course of these infections. Moreover, mixed infections of the same macrophage could be the basis for parasite recombination. We stained three strains of Leishmania (L. mexicana amazonensis, L. donovani DD8, and L. infantum D2, respectively) with different fluorescent dyes and analyzed them using a fluorescence-activated cell scanner. The simultaneous infection of one cell by Leishmania belonging to two different species was demonstrated. In additional experiments, cells with mixed infections were separated by a fluorescence-activated cell sorter and monitored for 24 hr. Preinfecting human monocytic U-937 cells with one Leishmania species did not exclude a second species added after 3 hr.

Comparison of different staining procedures for the flow cytometric analysis of U-937 cells infected with different Leishmania-species.

The human macrophage cell line U-937 infected with different Leishmania species, Leishmania mexicana amazonensis (Lma), Leishmania donovani (Ld) and Leishmania infantum (Li), was analyzed by flow cytometry (FCM). Leishmania spp. were labeled with different stains prior to the infection of the U-937 cells (BCECF-Am, PKH2-GL and SYTO 17) or after the infection (AO, FITC-conjugated monoclonal antibodies, PI). Infected cells were analyzed by flow cytometry, fluorescence microscopy and in parallel microscopically after Giemsa staining. The data obtained by these two methods were compared to decide which method is mostly appropriate for detection and estimation of the infection rate. Three fluorescent stains were suitable: BCECF-Am, SYTO 17 and FITC-conjugated MoAb with 0.02% digitonin. None of the vital stains gave evaluable results after 3 days of incubation.

A comparison of bone-related biomarkers and CA27.29 to assess response to treatment of osseous metastatic breast cancer.

BACKGROUND: The assessment of bone metastases by clinical examination or imaging techniques is still considered unreliable. We compared a specific marker of bone resorption, urinary deoxypyridinoline (DPD)-crosslinks, with serum calcium (Ca), alkaline phosphatase (AP) and CA27.29, to evaluate the status of bone metastases in patients with breast cancer. MATERIALS AND METHODS: Second morning voided urine was collected from 2 groups of patient (pts), those without evidence of disease (n = 118), and those with bone metastases (n = 85) under specific therapy plus pamidronate. DPD and CA27.29 were measured on the automated ACS180 system (Bayer Diagnostics, Tarrytown, NY, USA). Receiver operating characteristics (ROC) curves were established for each of the 4 biomarkers to determine whether they could distinguish the 2 subsets of pts with clinically sufficient validity, and to establish the corresponding cut-off values. RESULTS: Neither Ca nor AP was useful in discriminating the 2 subgroups. At a DPD cut-off of 13 nmol/mmol, we found a specificity of 69% and a sensitivity of 53% for diagnosing bone metastases. Best results, however, were seen for CA27.29. A cut-off value of 30 U/ml resulted in a specificity of 62% and a sensitivity of 81%. CONCLUSIONS: CA27.29 was the best parameter for the discrimination of stage IV breast cancer with bone metastases. The primary advantage of DPD lies in the monitoring of bone metastases under specific therapy.

The course of the urinary DPD-crosslink secretion in metastatic breast cancer--a possibility for response assessment.

BACKGROUND: Urinary deoxypyridinoline (DPD)-crosslinks have been shown to be a highly specific parameter for type I collagen metabolism. MATERIALS AND METHODS: In a prospective breast cancer study, urine samples were collected in after-care patients and in patients with bone metastases. DPD-crosslinks were measured every three weeks using a fully automated chemiluminescence immunoassay. Bone metastases were confirmed by bone scan and/or x-ray, and were followed-up over six months. To validate the test, a receiver operating characteristics (ROC)-curve was set up to find the DPD cut-off concentration which separates patients with no evidence of disease (NED) from patients with bone metastases. RESULTS: 73 breast cancer patients (41 with NED, 32 with bone metastases) were included into the ROC analysis. At a DPD cut-off value of 8 nmol/mmol creatinine, we found the best sensitivity (84.4%) for the detection of bone metastases with a specificity of 70.7%. Patients with stable bone disease under intravenous pamidronate treatment (90 mg q3w) and specific therapy had a significant (p = 0.007) fall of the DPD-crosslinks in comparison to the progressive subset with 72.7% falling below 8 nmol/mmol. CONCLUSIONS: We conclude that the net bone turnover is not increased at a DPD-crosslinks elimination < 8 nmol/mmol.

Neuropathy under chemotherapy.

Neuropathy is a dose-limiting side effect for a number of effective chemotherapeutic agents. A better understanding of effective mechanisms will lead to novel treatment strategies that will protect neurons without decreasing therapeutic efficacy. The assessment of the efficacy and neurotoxicity of various chemotherapeutic agents is vital, for a determination of the maximum allowable dose. The introduction of chemotherapy in the 50s and 60s of the twentieth century has resulted in the development of curative therapeutic interventions for patients with several types of solid tumours and hemopoietic neoplasms. The important obstacles encountered in the use of chemotherapy have been the toxicity to the normal tissue. During the past 8 years there has come about a new level of understanding of the mechanisms through which chemotherapeutic agents work. This has opened the door to new paradigms of treatment in which molecular, genetic, and biologic therapy can be used together to increase the sensitivity of abnormal cells to treatment, and to protect the normal tissues of the body from therapy-induced side effects. The implementation of new strategies could change the way therapy is delivered over the next few years and improve the outcome especially in patients with neoplasms that are currently resistant to conventional dose therapy.

Quality monitoring, standardized documentation and management with a computerized system in oncology.

Within the last years the prerequisite was prepared to develop a computerized tumor--patient documentation system including quality monitoring and oncological therapy recommendations for every day use. In medicine today, there is an increasing need for quality oriented low cost and transparent management--what is especially true in the field of oncology. The German Federal Authority of Health demands the documentation of all tumor disorders for the establishment of an cancer registry. For these reasons our study group established the program "OncoDoc" in cooperation with the laboratory for Artificial Intelligence of the University Bremen.

[Secondary malignancies in urinary diversions]. / Sekundärmalignome in Harnableitungen.

In contrast to ureterosigmoidostomy no reliable clinical data exist for tumor risk in different forms of urinary diversion using isolated intestinal segments.In 44 German urological departments, operation frequencies, indications, patient age, and operation dates of the different forms of urinary diversion, operated between 1970 and 2007, could be registered. The secondary tumors up to 2009 were registered as well and related to the numbers of the different forms of urinary diversions resulting in tumor prevalences.In 17,758 urinary diversions 32 secondary tumors occurred. The tumor risk in ureterosigmoidostomy (22-fold) and cystoplasty (13-fold) is significantly higher than in other continent forms of urinary diversion such as neobladders or pouches (p<0.0001). The difference between ureterosigmoidostomy and cystoplasty is not significant, nor is the difference between ileocecal pouches (0.14%) and ileal neobladders (0.05%) (p=0.46). The tumor risk in ileocecal (1.26%) and colonic neobladders (1.43%) is significantly higher (p=0.0001) than in ileal neobladders (0.5%). Of the 16 tumors that occurred following ureterosigmoidostomy, 16 (94%) developed directly at the ureterocolonic borderline in contrast to only 50% following urinary diversions via isolated intestinal segments.From postoperative year 5 regular endoscopic controls of ureterosigmoidostomies, cystoplasties, and orthotopic (ileo-)colonic neobladders are necessary. In ileocecal pouches, regular endoscopy is necessary at least in the presence of symptoms or should be performed routinely at greater intervals. Following neobladders or conduits, only urethroscopies for urethral recurrence are necessary.

Primary chemotherapy with gemcitabine as prolonged infusion, non-pegylated liposomal doxorubicin and docetaxel in patients with early breast cancer: final results of a phase II trial.

BACKGROUND: Combinations of anthracyclines, taxanes and gemcitabine have shown high activity in breast cancer. This trial was designed to evaluate a modified combination regimen as primary chemotherapy. Non-pegylated liposomal doxorubicin (NPLD) was used instead of conventional doxorubicin to improve cardiac safety. Gemcitabine was given 72 h after NPLD and docetaxel as a prolonged infusion over 4 h in order to optimize synergistic effects and accumulation of active metabolites. PATIENTS AND METHODS: Forty-four patients with histologically confirmed stage II or III breast cancer were treated with NPLD (60 mg/m(2)) and docetaxel (75 mg/m(2)) on day 1 and gemcitabine as 4-h infusion (350 mg/m(2)) on day 4. Treatment was repeated every 3 weeks for a maximum of six cycles. All patients received prophylactically recombinant granulocyte colony-stimulating factor. Patients with axillary lymph node involvement after primary chemotherapy received adjuvant treatment with cyclophosphamide, methotrexate and fluorouracil. RESULTS: The clinical response rate was 80%, and complete remissions of the primary tumor occurred in 10 patients (25%). Breast conservation surgery was performed in 19 out of 20 patients (95%) with an initial tumor size of less than 3 cm and in 14 patients (70%) with a tumor size

[Ptosis and ophthalmoplegia as predominant signs of multiple myeloma]. / Ptosis und Ophthalmoplegie als Leitsymptome eines multiplen Myeloms.

HISTORY AND ADMISSION FINDINGS: A 59-year-old woman was diagnosed as having solitary bone plasmacytoma of the sternum which was resected. Five month later she presented with a pathological fracture of the clavicle. On examination she had a ptosis and an ophthalmoplegia. INVESTIGATIONS: A mass in the clivus extending into the left sphenoid sinus as well as multiple osteolytic lesions in the skull were shown by cranial MRI. Skeletal survey showed multiple osteolytic lesions. Laboratory test did not show any specific abnormalities. DIAGNOSIS, TREATMENT AND COURSE: The biopsy taken from the mass at the sphenoid sinus demonstrated plasmacytoma. The diagnosis of multiple myeloma was based on the histological evidence of plasmacytoma and the occurrence of multiple lytic bone lesions although no infiltration of bone marrow and none of the specific laboratory findings were present. The patient underwent local radiotherapy with 30 Gy followed by systemic chemotherapy. The symptoms regressed completely under this therapy. CONCLUSION: Various cranial nerve syndromes such as the superior orbital fissure syndrome are most often caused by tumors at the skull base. Knowledge of the histological entity is essential for the correct diagnosis and the appropriate therapy because rare tumors like multiple myeloma may also cause such syndromes.

Simple high-performance liquid chromatographic method for the detection of phenylpropionylglycine in urine as a diagnostic tool in inherited medium-chain acyl-coenzyme A dehydrogenase deficiency.

Deficiency of medium-chain acyl-CoA dehydrogenase is a frequent and treatable metabolic defect, which can be diagnosed by detection of phenylpropionylglycine in urine after an oral load of phenylpropionic acid. We studied the determination of phenylpropionylglycine in urine by isocratic ion-exclusion chromatography on a cation-exchange column using water-sulphuric acid (pH values between 2 and 4) as mobile phase. Phenylpropionylglycine, phenylpropionic acid and hippuric acid exhibited high retention factors with only a slight decline at increasing solvent pH. This resulted in a good separation from interfering substances after direct injection of urine. We hypothesize that pi-pi interactions between the aromatic carbonic acids and the ion-exchange resin are responsible for the strong retention on the stationary phase. We conclude that, even in asymptomatic patients, determination of phenylpropionylglycine in urine after a phenylpropionic acid load by ion-exclusion chromatography is a rapid and reliable diagnostic tool for the detection of medium-chain acyl-CoA dehydrogenase deficiency.

[Therapeutic management of patients with metastasized breast carcinoma]. / Therapieführung bei Patientinnen mit metastasierten Mammakarzinomen.

In patients with metastasized breast cancer cure is beyond our therapeutic reach at present. In this situation the main treatment objectives are to improve existing or imminently threatening symptoms caused by the tumor growth, to retain or restore physical ability for as long as possible and, if possible, to prolong survival time. To achieve these treatment aims diphosphonates, hormones and cytotoxic mono- or polychemotherapy can be administered. The individualized administration of these drugs, adapted to the rate of the spread of metastases and tumor-induced symptoms, help to attain long survival without pronounced toxic side effects.