Quality of analgesic treatment in patients with advanced prostate cancer: do we do a better job now? The Swiss Group for Clinical Cancer Research (SAKK) experience

GOALS OF WORK: The aim of this study was to evaluate pain intensity and the application of the WHO guidelines for cancer pain treatment in patients with prostate cancer treated at Swiss cancer centers. MATERIALS AND METHODS: We analyzed a series of five multicenter phase II clinical trials which examined the palliative effect of different chemotherapies in patients with advanced hormone-refractory prostate carcinoma. Of 170 patients, 1,018 visits were evaluable for our purpose, including ratings of pain intensity by patients and prescribed analgesics. MAIN RESULTS: No or mild pain was indicated by patients in 36 to 55% of the visits, more than mild pain in 30 to 46%. In 21% of the visits, the WHO pain treatment criteria (treatment according to one of the three steps; oral, rectal or transdermal application of the main dose; administration on a regular schedule) were fulfilled, and the Cleeland index was positive according to all recommendations. In 6% of the visits, neither the WHO criteria were fulfilled nor was the Cleeland index positive. This indicates insufficient pain treatment not following the WHO guidelines and that the prescribed analgesics were not sufficiently potent for the rated pain intensity. CONCLUSIONS: In this selective Swiss sample, the standard of analgesic treatment is high. However, there is still scope for improvement. This cannot solely be solved by improving the knowledge of the physicians. Programs to change the patients' attitude towards cancer pain, training to improve the physicians' communication skills, and institutional changes may be promising strategies.

Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research

This randomized phase II trial evaluated two docetaxel-based regimens to see which would be most promising according to overall response rate (ORR) for comparison in a phase III trial with epirubicin-cisplatin-fluorouracil (ECF) as first-line advanced gastric cancer therapy.

Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group

This phase III trial compared the efficacy and safety of gemcitabine (Gem) plus capecitabine (GemCap) versus single-agent Gem in advanced/metastatic pancreatic cancer.

Multicenter phase II trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer (NSCLC): SAKK protocol 19/03

BACKGROUND: Gefitinib is active in patients with pretreated non-small-cell lung cancer (NSCLC). We evaluated the activity and toxicity of gefitinib first-line treatment in advanced NSCLC followed by chemotherapy at disease progression. PATIENTS AND METHODS: In all, 63 patients with chemotherapy-naive stage IIIB/IV NSCLC received gefitinib 250 mg/day. At disease progression, gefitinib was replaced by cisplatin 80 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1, 8 for up to six 3-week cycles. Primary end point was the disease stabilization rate (DSR) after 12 weeks of gefitinib. RESULTS: After 12 weeks of gefitinib, the DSR was 24% and the response rate (RR) was 8%. Median time to progression (TtP) was 2.5 months and median overall survival (OS) 11.5 months. Never smokers (n = 9) had a DSR of 56% and a median OS of 20.2 months; patients with epidermal growth factor receptor (EGFR) mutation (n = 4) had a DSR of 75% and the median OS was not reached after the follow-up of 21.6 months. In all, 41 patients received chemotherapy with an overall RR of 34%, DSR of 71% and median TtP of 6.7 months. CONCLUSIONS: First-line gefitinib monotherapy led to a DSR of 24% at 12 weeks in an unselected patients population. Never smokers and patients with EGFR mutations tend to have a better outcome; hence, further trials in selected patients are warranted.

MRI follow-up of TNF-dependent differential progression of atherosclerotic wall-thickening in mouse aortic arch from early to advanced stages

OBJECTIVES: An optimized, longitudinal in vivo magnetic resonance vessel wall-imaging protocol was evaluated regarding its capability of detecting differences in the time-dependent atherosclerotic lesion progression in the aortic arch between ApoE(-/-) and double-deficient ApoE(-/-)/TNF(-/-) mice at comparatively early plaque development stages. MATERIALS AND METHODS: Seven ApoE(-/-) and seven ApoE(-/-)/TNF(-/-) female mice underwent MRI at 11.75 teslas at four stages up to 26 weeks of age. A double-gated spin-echo MRI sequence was used with careful perpendicular slice positioning to visualize the vessel wall of the ascending aortic arch. RESULTS: Wall-thickness progression measured with MRI was significant at 11 weeks of age in ApoE(-/-) mice, but only at 26 weeks in ApoE(-/-)/TNF(-/-) mice. A significant correlation was found between MRI wall-thickness and lesion area determined on histology. CONCLUSION: MRI was shown to be sensitive enough to reveal subtle genetically-induced differences in lesion progression at ages earlier than 25 weeks.

Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis

BACKGROUND: Clinical outcomes of chronic hepatitis C infection in patients with advanced fibrosis include liver failure, hepatocellular carcinoma, and death. OBJECTIVE: To investigate whether sustained virologic response to treatment for hepatitis C is associated with improved clinical outcomes. DESIGN: Retrospective cohort study. SETTING: 5 hepatology units of tertiary care centers in Europe and Canada caring for patients with chronic hepatitis C treated between 1990 and 2003. PATIENTS: Consecutively treated patients with chronic hepatitis C who had biopsy-proven advanced fibrosis or cirrhosis (Ishak score, 4 to 6). MEASUREMENTS: Sustained virologic response, defined as absence of detectable hepatitis C virus RNA at 24 weeks after the end of treatment, and clinical outcomes, defined as death (liver-related or non-liver-related), liver failure, and hepatocellular carcinoma. RESULTS: Of 479 patients, 29.6% had sustained virologic response and 70.3% did not. Median follow-up was 2.1 years (interquartile range, 0.8 to 4.9 years). Four patients with and 83 without sustained virologic response had at least 1 outcome event. Sustained virologic response was associated with a statistically significant reduction in the hazard of events (adjusted hazard ratio, 0.21 [95% CI, 0.07 to 0.58]; P = 0.003). The effect was largely attributable to a reduction in liver failure, which developed in no patients with and 42 patients without sustained virologic response (5-year occurrence, 0% vs. 13.3% [CI, 8.4% to 18.2%]; unadjusted hazard ratio, 0.03 [CI, 0.00 to 0.91]). LIMITATIONS: Because few events occurred in the sustained virologic response group, the study had limited ability to detect differences between groups in individual outcomes. In addition, the study was retrospective; selection and survival biases may therefore influence estimates of effect. CONCLUSION: Sustained virologic response to treatment is associated with improved clinical outcomes, mainly prevention of liver failure, in patients with chronic hepatitis C and advanced fibrosis.

Arginine vasopressin in advanced cardiovascular failure during the post-resuscitation phase after cardiac arrest

Arginine vasopressin (AVP) has been employed successfully during cardiopulmonary resuscitation, but there exist only few data about the effects of AVP infusion for cardiovascular failure during the post-cardiac arrest period. Cardiovascular failure is one of the main causes of death after successful resuscitation from cardiac arrest. Although the "post-resuscitation syndrome" has been described as a "sepsis-like" syndrome, there is little information about the haemodynamic response to AVP in advanced cardiovascular failure after cardiac arrest. In this retrospective study, haemodynamic and laboratory variables in 23 patients with cardiovascular failure unresponsive to standard haemodynamic therapy during the post-cardiac arrest period were obtained before, and 30 min, 1, 4, 12, 24, 48, and 72 h after initiation of a supplementary AVP infusion (4 IU/h). During the observation period, AVP significantly increased mean arterial blood pressure (58+/-14 to 75+/-19 mmHg, p < 0.001), and decreased noradrenaline (norepinephrine) (1.31+/-2.14 to 0.23+/-0.3 microg/kg/min, p = 0.03), adrenaline (epinephrine) (0.58+/-0.23 to 0.04+/-0.03 microg/kg/min, p = 0.001), and milrinone requirements (0.46+/-0.15 to 0.33+/-0.22 microg/kg/min, p < 0.001). Pulmonary capillary wedge pressure changed significantly (p < 0.001); an initial increase being followed by a decrease below baseline values. While arterial lactate concentrations (95+/-64 to 21+/-18 mg/dL, p < 0.001) and pH (7.27+/-0.14 to 7.4+/-0.14, p < 0.001) improved significantly, total bilirubin concentrations (1.12+/-0.95 to 3.04+/-3.79 mg/dL, p = 0.001) increased after AVP. There were no differences in the haemodynamic or laboratory response to AVP between survivors and non-survivors. In this study, advanced cardiovascular failure that was unresponsive to standard therapy could be reversed successfully with supplementary AVP infusion in >90% of patients surviving cardiac arrest.

Advanced chronic heart failure: A position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology

Therapy has improved the survival of heart failure (HF) patients. However, many patients progress to advanced chronic HF (ACHF). We propose a practical clinical definition and describe the characteristics of this condition. Patients that are generally recognised as ACHF often exhibit the following characteristics: 1) severe symptoms (NYHA class III to IV); 2) episodes with clinical signs of fluid retention and/or peripheral hypoperfusion; 3) objective evidence of severe cardiac dysfunction, shown by at least one of the following: left ventricular ejection fraction<30%, pseudonormal or restrictive mitral inflow pattern at Doppler-echocardiography; high left and/or right ventricular filling pressures; elevated B-type natriuretic peptides; 4) severe impairment of functional capacity demonstrated by either inability to exercise, a 6-minute walk test distance<300 m or a peak oxygen uptake<12-14 ml/kg/min; 5) history of >1 HF hospitalisation in the past 6 months; 6) presence of all the previous features despite optimal therapy. This definition identifies a group of patients with compromised quality of life, poor prognosis, and a high risk of clinical events. These patients deserve effective therapeutic options and should be potential targets for future clinical research initiatives.

Patient-reported outcomes of patients with advanced biliary tract cancers receiving gemcitabine plus capecitabine: a multicenter, phase II trial of the Swiss Group for Clinical Cancer Research

PURPOSE: To evaluate the effects of palliative chemotherapy with gemcitabine plus capecitabine (GemCap) on patient-reported outcomes measured using clinical benefit response (CBR) and quality-of-life (QOL) measures in patients with advanced biliary tract cancer. PATIENTS AND METHODS: Patients had to manifest symptoms of advanced biliary tract cancer and have at least one of the following: impaired Karnofsky performance score (60 to 80), average analgesic consumption >or= 10 mg of morphine equivalents per day, and average pain intensity score of >or= 20 mm out of 100 mm. Treatment consisted of oral capecitabine 650 mg/m(2) twice daily on days 1 through 14 plus gemcitabine 1,000 mg/m(2) as a 30-minute infusion on days 1 and 8 every 3 weeks until progression. The primary end point was the number of patients categorized as having a CBR or stable CBR (SCBR) during the first three treatment cycles. RESULTS: Forty-four patients were enrolled (bile duct cancer, n = 36; gallbladder cancers, n = 8). The main grade 3 or 4 adverse events included hematologic toxicity and fatigue. After three cycles, 36% of patients achieved a CBR, and 34% achieved an SCBR. Over the full course of treatment, 57% of patients achieved a CBR, and 18% achieved an SCBR. Improved QOL was observed in patients with a CBR or SCBR. The objective response rate was 25%. Median time to progression and overall survival times were 7.2 months and 13.2 months, respectively. CONCLUSION: Chemotherapy with GemCap is well tolerated and effective and leads to a high CBR rate. Patient-reported outcomes are useful for evaluating the effects of palliative chemotherapy in patients with biliary tract cancer.

Advanced mechanics of materials with microstructure

The study of advanced materials aimed at improving human life has been performed since time immemorial. Such studies have created everlasting and greatly revered monuments and have helped revolutionize transportation by ushering the age of lighter–than–air flying machines. Hence a study of the mechanical behavior of advanced materials can pave way for their use for mankind’s benefit. In this school of thought, the aim of this dissertation is to broadly perform two investigations. First, an efficient modeling approach is established to predict the elastic response of cellular materials with distributions of cell geometries. Cellular materials find important applications in structural engineering. The approach does not require complex and time-consuming computational techniques usually associated with modeling such materials. Unlike most current analytical techniques, the modeling approach directly accounts for the cellular material microstructure. The approach combines micropolar elasticity theory and elastic mixture theory to predict the elastic response of cellular materials. The modeling approach is applied to the two dimensional balsa wood material. Predicted properties are in good agreement with experimentally determined properties, which emphasizes the model’s potential to predict the elastic response of other cellular solids, such as open cell and closed cell foams. The second topic concerns intraneural ganglion cysts which are a set of medical conditions that result in denervation of the muscles innervated by the cystic nerve leading to pain and loss of function. Current treatment approaches only temporarily alleviate pain and denervation which, however, does not prevent cyst recurrence. Hence, a mechanistic understanding of the pathogenesis of intraneural ganglion cysts can help clinicians understand them better and therefore devise more effective treatment options. In this study, an analysis methodology using finite element analysis is established to investigate the pathogenesis of intraneural ganglion cysts. Using this methodology, the propagation of these cysts is analyzed in their most common site of occurrence in the human body i.e. the common peroneal nerve. Results obtained using finite element analysis show good correlation with clinical imaging patterns thereby validating the promise of the method to study cyst pathogenesis.