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.

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.

[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

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.

[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.

Differentiation of a pancreatic metastasis of a renal cell carcinoma from a primary pancreatic carcinoma by echo-enhanced power Doppler sonography.

In a 70-year-old patient who had been treated for a renal cell carcinoma, a pancreatic mass was detected on CT scan. To differentiate a pancreatic metastasis of the renal cell carcinoma from a pancreatic carcinoma, an echo-enhanced power Doppler sonography was performed. The pancreatic mass demonstrated a strong echo enhancement, proving its hypervascularization. This behaviour favoured the diagnosis of a pancreatic metastasis of the renal cell carcinoma which was confirmed by histology. The principles and the role of echo-enhanced power Doppler sonography in the differential diagnosis between a primary pancreatic carcinoma and a metastasis of a renal carcinoma in the pancreas are discussed. We conclude that this technique can provide an important contribution to the diagnosis in this special instance. However, histology is the standard in the differential diagnosis of pancreatic tumours.

Development of a flow cytometric method to determine DNA ploidy of oesophageal cancer cells obtained by forceps biopsy samples during oesophago-gastro-duodenoscopy.

BACKGROUND: The DNA content of oesophageal tumour cells is a prognostic factor in untreated patients. To investigate whether DNA ploidy is useful to select patients for neoadjuvant therapy it is of interest to develop a method allowing reliable flow cytometric analysis of the DNA content of tumour cells obtained by forceps biopsy during endoscopy before start of therapy. METHODS: Freshly frozen forceps biopsy samples from 30 patients with oesophageal cancer were disaggregated. DNA was stained with propidium iodide and ploidy was determined by flow cytometry. To enhance sensitivity epithelial cells were simultaneously labelled with anti-cytokeratin antibodies. Results were compared with image analysis. To evaluate the sampling error, parallel measurements were done in 10 patients by image analysis on forceps biopsies obtained during endoscopy before surgery and on the resected tumour. RESULTS: The sensitivity to detect aneuploidy was lower for standard flow cytometry than for image analysis (13 versus 33%). The overall sensitivities were identical using a double labelling technique with additional cytokeratin-staining of the epithelial cells, but divergent results were obtained in 2 cases, where detection of aneuploidy was either possible with image analysis or with double labelling flow cytometry only. DNA content of samples gained by forceps biopsies and surgically resected tumours was concordant in 8 of 10 cases. In 2 patients, aneuploidy was detected only in the surgically resected tumour but not in the pre-operatively obtained forceps biopsies. CONCLUSIONS: A flow cytometric method for routine determination of the DNA ploidy of cells obtained by forceps biopsies from patients with oesophageal cancer was developed and evaluated against image analysis. The technique allows the prediction of DNA content before tumour resection, and might be used for optimising therapy and the patient's quality of live.

[Pancreatic metastases of renal cell carcinomas - evaluation of the contrast behavior at echo-enhanced power-Doppler sonography in comparison to primary pancreatic tumors]. / Nierenzellkarzinom-Metastasen des Pankreas - Evaluierung ihres Kontrastverhaltens in der echosignalverstärkten Power-Doppler-Sonographie im Vergleich mit primären Pankreastumoren.

BACKGROUND: Renal cell carcinomas are the most common primary tumors leading to pancreatic metastases. The differentiation of metastases from primary pancreatic tumors is important for the prognosis. Echo-enhanced power-Doppler sonography may be used for the differential diagnosis of tumors. In this study, the contrast behavior of metastases of renal cell carcinomas was evaluated in comparison to primary pancreatic tumors. PATIENTS AND METHODS: Each 5 patients with pancreatic metastases of a renal cell carcinoma, a ductal carcinoma, a neuroendocrine tumor and a pancreatitis-associated mass were investigated by B-mode sonography, fundamental and echo-enhanced power-Doppler sonography. RESULTS: Similar to neuroendocrine tumors, metastases of renal cell carcinomas were found to be hypervascularized. In contrast, ductal carcinomas are hypovascularized compared to the surrounding tissue. Tumors associated with pancreatitis show different vascularization pattern depending on inflammation and necrosis. CONCLUSIONS: Metastases of renal cell carcinomas and ductal carcinomas show different vascularization pattern at echo-enhanced power-Doppler sonography. Renal cell metastases and neuroendocrine tumors have similar contrast behaviors, therefore, clinical symptoms should be referred for their differentiation. However, histology is the standard of reference for the differential diagnosis of pancreatic tumors.

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.

An unusual case of leukemic non-Hodgkin's lymphoma with blastic transformation.

We report on a patient who was diagnosed as having B-cell chronic lymphocytic leukemia (CLL) with atypical morphology. Flow cytometry disclosed CD5, CD19, and CD23 positivity, an immunophenotype seen mostly in B-CLL. Histology of the spleen and bone marrow suggested a diagnosis of small lymphocytic lymphoma. Upon blastic transformation, only 3 years after the diagnosis had been made, unusual clinical and laboratory features emerged. Lymphoid blasts appeared in the peripheral blood, and the patient developed nodular infiltrates consisting of these blasts at recent venous puncture sites. The patient did not respond to chemotherapy and died. The lymphoid blasts in the peripheral blood were CD5-, CD19+, and CD23+ and harbored t(11;14) (q13;q32) and t(11;21)(p11;q21) translocations. To account for the possibility of two independent lymphoid malignancies, molecular genetic analyses were performed on samples from the spleen, bone marrow and a lymph node with the large-cell lymphoma, which showed identical clones in these tissues. This unusual case supports the idea that in leukemic non-Hodgkin's lymphoma, in addition to morphology, an accurate diagnostic workup requires immunophenotypic, cytogenetic, and molecular studies.

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.

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 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. In a previous phase I trial the maximum tolerated dose of gemcitabine given as a 6 h i.v. infusion was 250 mg/m2. The objective of this phase II trial was to determine the efficacy and safety of gemcitabine as prolonged infusion in patients with metastatic breast cancer. Twenty patients [median age 50.4 years, range 35-63 years; performance status EORTC 0 (17 patients), 1 (two patients), 2 (one patient)] with metastatic breast cancer were treated with 250 mg/m2 gemcitabine as infusion over 6 h on days 1, 8 and 15 q3 weeks for up to six courses (median 3.9 courses). Treatment was first line for four patients, second line for five patients and third line or higher for 11 patients. Metastatic sites were liver in 14 patients, bone in 12 patients, lung in eight patients and lymph nodes in nine patients. Nine patients presented two metastatic sites, three patients three and five patients four. All patients were evaluable for response and toxicity. One patient (5%) achieved a complete remission (CR) and four patients (20%) a partial remission (PR) (one patient with CR of visceral metastases but stable bone metastases), for an overall response rate of 25% (five of 20). In addition, six patients (30%) had stable disease and nine (45%) failed to respond to the treatment. Time to progression ranged from 2 to 23 months with a median of 6.3 months. Hematologic toxicity was mild with leukopenia grade 3 in only three patients (15%) and no grade 3 thrombocytopenia. Moderate elevations of liver enzymes (three patients grade 3), nausea and vomiting (two patients grade 2), and mild alopecia were observed, but only one patient had to be withdrawn due to toxicity. In conclusion gemcitabine as prolonged infusion is an effective treatment in metastatic breast cancer. Toxicity, especially myelosuppression, is surprisingly mild. Therefore, gemcitabine seems to be ideal for combination therapies.

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.

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.

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.