Distinct patterns of angiogenic factor expression as a predictive factor of response to chemotherapy in stage IIIA non-small-cell lung cancer patients.

The expression of various angiogenic factors was assessed in tumour samples of patients with stage III non-small-cell lung cancer (NSCLC) and further evaluated in terms of response to induction paclitaxel-ifosfamide-cisplatin chemotherapy. Freshly isolated lung tumour specimens obtained by bronchoscopy from 70 stage IIIA NSCLC chemotherapy-naïve patients were sampled and analysed for vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2 and VEGFR-3. Microvessel density was assessed through evaluating the angiogenic markers CD34 and CD105. Immunostaining scores were calculated by multiplying the percentage of labeled cells by the intensity of staining for each examined parameter. The overall mean immunostaining score value from all NSCLC samples was 7.83, 5.56 and 15.86 for VEGFR-1, VEGFR-2 and VEGFR-3, respectively. The overall mean value of the endothelial antigen CD34 was 16.29, whereas the expression of the CD105 antigen in endothelial cells yielded a multivariate distribution. Patients who responded to chemotherapy expressed significantly higher VEGFR-1 and VEGFR-3 mean values compared with non-responders (P<0.001). No significant difference was noted in VEGFR-2 mean values between these two groups (P=0.06). The CD34 mean value was significantly higher in responders (P<0.001), whereas there was no significant difference in CD105 expression between the two groups (P=0.07). Angiogenic marker expression proved to be a potential predictive factor of response to chemotherapy in stage III NSCLC. which merits further investigation.

Prior exposure to chemotherapy: a marker of sensitivity and selection for antiangiogenic therapy in breast cancer?

The identification of patients who are more likely to derive benefit from antiangiogenic therapy is a key to refine patient selection and so maximize clinical benefit, and reduce unnecessary treatment costs. Improved patient selection will equally be effective in minimizing the exposure of non-eligible patients to ineffectual treatment which could be associated with adverse effects as well as delaying effective treatment. Herein, we review the literature from clinical trials suggesting that the addition of antiangiogenic agents to chemotherapy for the treatment of HER-2 negative metastatic breast cancer in patients previously exposed to chemotherapy may deliver differential therapeutic benefit and may serve as a selection criteria in the current absence of a robust biomarker.

Modulation of peripheral immune responses by paclitaxel-ifosfamide-cisplatin chemotherapy in advanced non-small-cell lung cancer.

PURPOSE: The aim of this study was to assess systemic immunological responses in non-small-cell lung cancer (NSCLC) patients with stage III/IV disease during treatment with paclitaxel-ifosfamide-cisplatin (TIP) chemotherapy. METHODS: Peripheral blood mononuclear cells (PBMCs) collected from healthy donors (HD) (n = 20) and chemotherapy-naive NSCLC patients treated with TIP (n = 32) were tested for production of IL-1, TNF-α, TNF-ß, IL-6, IL-8, IL-10, IL-12 and IL-2 upon polyclonal stimulation with anti-CD3 mAb. They were further assessed over a treatment period of twelve weeks (i.e., four treatment cycles). RESULTS: PBMCs from NSCLC patients produced higher IL-1, TNF-α, TNF-ß, IL-6, IL-8, IL-10 and IL-12 levels, whereas IL-2 exhibited lower values compared to HD (p < 0.001 for all parameters). Of interest, patients who responded to treatment had significantly higher increases in IL-2 (p < 0.001) and significantly higher decreases in IL-1 (p < 0.001), TNF-α (p < 0.001), TNF-ß (p < 0.001), IL-6 (p = 0.02), IL-8 (p < 0.001), IL-10 (p < 0.001) and IL-12 (p < 0.001) levels. Non-responders revealed post-therapeutically a significantly higher increase in IL-1, TNF-α, TNF-ß, IL-6, IL-8, IL-10 and IL-12 secretion and a significantly higher decrease in IL-2 levels (p < 0.001 for all parameters). Patients who responded to treatment and had a significantly higher increase in IL-2 showed a significantly longer median survival (p value < 0.001, 26 vs. 7.5 months). CONCLUSION: Our study indicates that monitoring cytokine dynamics in patients with advanced NSCLC and especially those of IL-2 in peripheral blood components in vitro could be used as a predictor of treatment-related outcome and overall survival in NSCLC.

Pregabalin for opioid-refractory pain in a patient with ankylosing spondylitis.

Background. Ankylosing spondylitis (AS) is a systemic inflammatory disease with chronic back pain as the most common presenting symptom. We present a case of a male patient with AS reporting symptoms of severe low back pain, buttock pain, and limited spinal mobility. After chronic treatment with opioids, we administered pregabalin at a dose of 300 mg as an analgesic agent while opioids were discontinued. Findings. Pain symptoms improved progressively, and opioids were gradually discontinued without any withdrawal symptoms reported. Conclusions. Pregabalin is potentially useful in the management of pain in patients with AS while effectively managing the discontinuation of opioid treatment.

Factors Influencing Survival in Stage IV Colorectal Cancer: The Influence of DNA Ploidy.

Objective. To evaluate the prognostic significance of microscopically assessed DNA ploidy and other clinical and laboratory parameters in stage IV colorectal cancer (CRC). Methods. 541 patients with histologically proven stage IV CRC treated with palliative chemotherapy at our institution were included in this retrospective analysis, and 9 variables (gender, age, performance status, carcinoembryonic antigen, cancer antigen 19-9, C-Reactive Protein (CRP), anaemia, hypoalbuminaemia, and ploidy (DNA Index)) were assessed for their potential relationship to survival. Results. Mean survival time was 12.8 months (95% confidence interval (CI) 12.0-13.5). Multivariate analysis revealed that DNA indexes of 2.2-3.6 and >3.6 were associated with 2.94 and 4.98 times higher probability of death, respectively, compared to DNA index <2.2. CRP levels of >15 mg/dL and 5-15 mg/dL were associated with 2.52 and 1.72 times higher risk of death, respectively. Hazard ratios ranged from 1.29 in patients mild anaemia (Hb 12-13.5 g/dL) to 1.88 in patients with severe anaemia (Hb < 8.5 g/dL). Similarly, the presence of hypoalbuminaemia (albumin < 5 g/dL) was found to confer 1.41 times inferior survival capability. Conclusions. Our findings suggest that patients with stage IV CRC with low ploidy score and CRP levels, absent or mild anaemia, and normal albumin levels might derive greatest benefit from palliative chemotherapy.

Chemotherapy ± cetuximab modulates peripheral immune responses in metastatic colorectal cancer.

OBJECTIVE: To identify changes in peripheral immune responses in patients with metastatic colorectal cancer (mCRC) treated with irinotecan/5-fluorouracil/leucovorin (IFL) alone or in combination with cetuximab (C-IFL). METHODS: Peripheral blood mononuclear cells (PBMCs) collected from healthy donors (n = 20) and patients with mCRC receiving treatment with either IFL (n = 30) or C-IFL (n = 30) were tested for cytokine production upon polyclonal stimulation with anti-CD3 monoclonal antibody, T cell proliferation in the autologous mixed lymphocyte reaction (auto-MLR) and T regulatory cell (Treg) frequency. The respective results were evaluated over two treatment cycles and further assessed in relation to response to treatment. RESULTS: PBMCs prior to treatment exhibited significantly lower production of IL-2, IFN-γ, IL-12 and IL-18 cytokines and lower auto-MLR responses, whereas Treg frequency, IL-4, IL-10 cytokines were increased compared to healthy donors. During treatment, IL-2, IFN-γ, IL-12, IL-18 and auto-MLR responses increased, while Treg frequency and IL-10 secretion decreased significantly compared to the baseline. Responders to treatment exhibited a significantly higher increase in IL-2, IFN-γ, IL-12 and IL-18 production and auto-MLR responses, and higher decrease in IL-4, IL-10 secretion and Treg frequency. Among all patient subgroups analysed, responders to C-IFL demonstrated significantly higher increase in auto-MLR responses, IL-12 and IL-18 secretion and higher decrease in Treg frequency. CONCLUSION: The disturbed immune parameters observed in patients with mCRC at presentation can be significantly improved during treatment with IFL and this effect can be potentiated by the addition of cetuximab. Monitoring of the peripheral immune system function could be used as surrogate marker in predicting treatment-related outcome.

DNA ploidy: a prognostic factor of response to chemotherapy and survival in metastatic gastric adenocarcinoma.

BACKGROUND: Metastatic gastric adenocarcinoma confers a dismal prognosis. Several prognostic factors are needed to distinguish patients that will benefit from chemotherapy. In this setting, the prognostic impact of DNA ploidy is still unclear. MATERIALS AND METHODS: The records of 61 patients with metastatic gastric adenocarcinoma were retrospectively reviewed. Response to chemotherapy and overall survival (OS) were assessed and correlated to tumour DNA ploidy index, which was calculated by cytometric image analysis. RESULTS: The median value of DNA ploidy index was 2.3. Patients with a low index responded better to chemotherapy than those with a higher index (p<0.01). Nevertheless, when the median value was used as a cut-off, no significant correlation of DNA ploidy index with response to chemotherapy (p=0.41) or OS (p=0.09) was observed. CONCLUSION: The prognostic role of DNA ploidy in metastatic gastric adenocarcinoma is still debatable. In this study, a low DNA ploidy index was associated with favorable prognosis; however, a suitable cut-off value is not yet available.

Survival in patients with stage IV noncardia gastric cancer - the influence of DNA ploidy and Helicobacter pylori infection.

BACKGROUND: Palliative surgery followed by postoperative chemotherapy is a challenging approach in the treatment of stage IV gastric cancer yet patients must be carefully selected on the basis of likely clinical benefit. METHODS: The records of 218 patients with histological diagnosis of gastric adenocarcinoma who underwent palliative surgery followed by postoperative chemotherapy were retrospectively reviewed. Twelve potential prognostic variables including tumour DNA index and serum IgG anti- Helicobacter pylori (HP) antibodies were evaluated for their influence on overall survival by multivariate analysis. RESULTS: The median survival was 13.25 months [95% Confidence Interval (CI) 12.00, 14.50]. Three factors were found to have an independent effect on survival: performance status (PS) [PS 60-70 vs. 90-100 Hazard Ratio (HR) 1.676; CI 1.171-2.398, p = 0.005], liver metastases (HR 1.745; CI 1.318-2.310, p < 0.001), and DNA Index as assessed by Image cytometry (2.2-3.6 vs. >3.6 HR 3.059; CI 2.185-4.283, p < 0.001 and <2.2 vs. >3.6 HR; 4.207 CI 2.751-6.433 <0.001). HP infection had no statistically significant effect on survival by either univariate or multivariate analysis. CONCLUSION: Poor pre-treatment PS, the presence of liver metastasis and high DNA Index were identified factors associated with adverse survival outcome in patients with Stage IV gastric cancer treated with palliative gastrectomy and postoperative chemotherapy. HP infection had no influence on survival of these patients.

Pancreatic adenocarcinoma-associated polymyositis treated with corticosteroids along with cancer specific treatment: case report.

BACKGROUND: Adenocarcinoma of the pancreas only rarely is associated with inflammatory myopathy. In this setting, polymyositis may be treated with glucocorticoids in combination with cancer specific treatment. CASE PRESENTATION: We present the case of a 52-year-old man with stage IIA pancreatic tail adenocarcinoma who underwent surgical treatment and six months into therapy with gemcitabine he developed symmetrical, painful, proximal muscle weakness with peripheral oedema. Re-evaluation with imaging modalities, muscle histology and biochemistry conferred the diagnosis of polymyositis associated with pancreatic cancer progression. The patient was treated with glucocorticoids along with gemcitabine and erlotinib which resulted in complete remission within six months. He remained in good health for a further six months on erlotinib maintenance therapy when a new computer tomography scan showed pancreatic cancer relapse and hence prompted 2nd line chemotherapy with gemcitabine. CONCLUSIONS: Polymyositis associated with pancreatic cancer may respond to glucocorticoids along with cancer specific treatment.

Pituitary insufficiency after infectious meningitis: a prospective study.

CONTEXT: Data from previous retrospective studies and case reports have suggested that infectious diseases of the central nervous system could cause pituitary deficiency. OBJECTIVE: The aim of this prospective study was to investigate pituitary function in patients admitted with infectious meningitis during the acute phase and after 12 months. DESIGN: Sixteen patients were studied. Basal pituitary function was assessed within 24 h of admission. Twelve of these patients underwent both basal and stimulated (insulin tolerance test) pituitary testing after 12 months. RESULTS: During the acute phase, five patients (31.25%) showed apparent pituitary hormone deficiencies: two patients with gonadotropic and three patients with somatotropic deficiency. The exact status of corticosteroid sufficiency could not be defined in four patients, because no dynamic test was performed in the acute phase. In addition, seven patients (44%) had probable low T(3) syndrome. At 12 months, five patients (31.25%), two with viral and three with bacterial meningitis, had at least one anterior pituitary hormone deficiency. Two patients had isolated corticotropic and one isolated somatotropic deficiency. Combined corticotropic and somatotropic deficiencies were detected in two patients. New-onset deficiencies accounted for four of those five patients, whereas one patient demonstrated persisting somatotropic deficiency. All cases of low T(3) syndrome resolved at 12 months. CONCLUSIONS: Isolated or combined pituitary deficiencies, which could present at the acute phase and/or occur at a later stage, can develop in a considerable proportion of patients after acute infectious meningitis.

Predictors of survival in stage IV metastatic colorectal cancer.

UNLABELLED: The aim of this study was to evaluate predictors of survival in stage IV metastatic colorectal cancer (CRC). PATIENTS AND METHODS: A total of 541 patients with histologically proven metastatic CRC (UICC stage IV) were retrospectively analysed and 37 variables were tested for their potential relationship to survival. RESULTS: Mean survival time was recorded at 12.8 months [95% confidence interval (CI) 12.0-13.5]. Three factors were independently associated with improved survival: combination chemotherapy, improved performance status and dermatological complications. Eight factors were independently associated with unfavorable survival: worsened performance status, C-reactive protein >5 mg/dl, anemia, anorexia, weight loss > or =10%, fatigue, hypoalbuminemia and blood transfusions. CONCLUSION: A number of factors could be used as predictors of survival in patients with stage IV metastatic CRC. Patients who are relatively fit, have low CRP levels and tolerate combination chemotherapy appear to have a more favorable survival outcome.

Hypercalcemia in a patient with cholangiocarcinoma: a case report.

BACKGROUND: Humoral hypercalcemia of malignancy is rarely associated with cholangiocarcinoma (CC). CASE REPORT: A 77-year-old man was admitted with confusion. Computer tomography showed a large multinodular mass in the right lobe of the liver and smaller lesions in the right lung. Liver histology confirmed the diagnosis of CC. Elevated calcium levels and suppressed intact parathyroid hormone in the absence of skeletal metastases or parathyroid gland pathology suggested the diagnosis of humoral hypercalcemia of malignancy (HHM). Treatment of hypercalcemia with saline infusion, loop diuretics, biphosphonate and calcitonin was effective in normalizing calcium levels and consciousness state within 48 hours, but a relapse occurred 4 weeks later and the patient succumbed to his disease. CONCLUSION: Clinicians should be aware of this rare manifestation of CC as prompt and aggressive correction of hypercalcemia alleviates symptoms and improves patient's quality of life, despite the poor overall prognosis.

Evaluation of DNA ploidy in relation with established prognostic factors in patients with locally advanced (unresectable) or metastatic pancreatic adenocarcinoma: a retrospective analysis.

BACKGROUND: Most patients with ductal pancreatic adenocarcinoma are diagnosed with locally advanced (unresectable) or metastatic disease. The aim of this study was to evaluate the prognostic significance of DNA ploidy in relation with established clinical and laboratory variables in such patients. METHODS: Two hundred and twenty six patients were studied retrospectively. Twenty two potential prognostic variables (demographics, clinical parameters, biochemical markers, treatment modality) were examined. RESULTS: Mean survival time was 38.41 weeks (95% c.i.: 33.17-43.65), median survival 27.00 weeks (95% c.i.: 23.18-30.82). On multivariate analysis, 10 factors had an independent effect on survival: performance status, local extension of tumor, distant metastases, ploidy score, anemia under epoetin therapy, weight loss, pain, steatorrhoea, CEA, and palliative surgery and chemotherapy. Patients managed with palliative surgery and chemotherapy had 6.7 times lower probability of death in comparison with patients without any treatment. Patients with ploidy score > 3.6 had 5.0 times higher probability of death in comparison with patients with ploidy score < 2.2 and these with ploidy score 2.2-3.6 had 6.3 times higher probability of death in comparison with patients with ploidy score < 2.2. CONCLUSION: According to the significance of the examined factor, survival was improved mainly by the combination of surgery and chemotherapy, and the presence of low DNA ploidy score.

Leishmaniasis, autoimmune rheumatic disease, and anti-tumor necrosis factor therapy, Europe.

We report 2 cases of leishmaniasis in patients with autoimmune rheumatic diseases in Greece. To assess trends in leishmaniasis reporting in this patient population, we searched the literature for similar reports from Europe. Reports increased during 2004-2008, especially for patients treated with anti-tumor necrosis factor agents.