Quality of life during chemotherapy in lung cancer patients: results across different treatment lines.

BACKGROUND: Most lung cancer patients are diagnosed at an advanced disease stage and predominantly receive palliative treatment, which increasingly consists of several chemotherapy lines. We report on patients' quality of life (QOL) to gain knowledge on QOL during and across multiple lines of chemotherapy. This includes patients with (neo)adjuvant therapy up to 3rd or above line palliative chemotherapy. METHODS: Lung cancer patients receiving outpatient chemotherapy at the Kufstein County Hospital completed an electronic version of the EORTC QLQ-C30. Linear mixed models were used for statistical analysis. RESULTS: One hundred and eighty seven patients were included in the study. Surprisingly, irrespective of the chemotherapy line patients reported stable QOL scores during treatment. None of the calculated monthly change rates attained clinical significance, referring to established guidelines that classify a small clinical meaningful change as 5 to 10 points. According to treatment line, 3rd or above line palliative chemotherapy was associated with the worst QOL scores, whereas patients undergoing (neo)adjuvant or 1st line palliative chemotherapy reported fairly comparable QOL. CONCLUSION: The essential finding of our study is that all QOL aspects of the EORTC QLQ-C30 questionnaire remained unchanged during each chemotherapy line in an unselected population of lung cancer patients. Between treatment lines pronounced differences were found, indicating that later palliative chemotherapy lines are associated with higher QOL impairments. These changes in QOL may not primarily be related to the treatment, but rather refer to impairments due to disease progression and may be partly due to a consequence of the prior therapies.

Feasibility of a multdisciplinary lung cancer videoconference between a peripheral hospital and a comprehensive cancer centre.

OBJECTIVE: Treatment of lung cancer patients is changing rapidly and new treatment options have emerged in recent years. In 2007, to guarantee the best treatment procedure for lung cancer patients being treated in our peripheral hospital, we decided to introduce an interdisciplinary tumour videoconference between the Haemato-Oncological Day Hospital in Merano and the Comprehensive Cancer Centre Innsbruck. This retrospective analysis aims to describe the feasibility of such a conference. PATIENTS AND METHODS: Two hundred and three patients with lung cancer treated at the peripheral hospital of Merano between May 2003 until May 2011 were retrospectively analysed. After introduction of the tumour videoconference in 2007, 54% (n = 110) of the patients in this cohort were discussed in the conference. RESULTS: One hundred and four videoconferences were performed. Videoconference was feasible for 110 patients. Radiotherapeutic treatments were prescribed more frequently in patients from the conference group. Overall, major and minor treatment changes were undertaken in 7% (n = 8) and 18% (n = 20), respectively. CONCLUSION: Interdisciplinary tumour videoconference is feasible between a peripheral hospital and a comprehensive cancer centre. Radiotherapeutic treatment was prescribed more frequently, suggesting that such a conference facilitates the access to cancer-centre-specific treatment modalities. Accordingly, tumour videoconference between a peripheral hospital and a cancer centre is to be recommend.

Purine antagonists for chronic lymphocytic leukaemia.

BACKGROUND: Recent trials suggest improved response rates for purine antagonists compared to alkylator-based regimens in the treatment of B-CLL. However, none was able to show a survival advantage. OBJECTIVES: To determine if there is any advantage of purine antagonists compared to alkylating agents (alone or in combination) in the treatment of patients with previously untreated B-CLL. SEARCH STRATEGY: Medical databases (Cochrane Library, MEDLINE, EMBASE), conference proceedings and internet-based trial registers were searched electronically and/or by hand (1990-2003). All references were checked for further trial information. We also contacted experts in the field and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials comparing purine antagonists as single agents with alkylator-based regimens in patients with previously untreated B-CLL were included. We included full-text and abstract publications as well as unpublished data. DATA COLLECTION AND ANALYSIS: Data extraction and quality assessment were done in duplicate by two independent reviewers. Missing data were obtained from original authors. Endpoints included overall survival, overall response rate, rate of complete remissions, progression-free survival, treatment-related morbidity and mortality. MAIN RESULTS: Five trials with 1838 randomised patients were included. There is some evidence for improved overall survival after treatment with purine antagonists compared to alkylators, but statistical significance was not reached (HR 0.89 [95% CI 0.78-1.01], 4 trials, n=1638). However, the relative risk for achieving an overall response (RR 1.22 [95% CI 1.13-1.31], 5 trials, n=1751) and complete remission (RR 1.94 [95% CI 1.65-2.28], 5 trials, n=1751) was significantly higher, resulting in a longer progression-free survival (HR 0.70 [95% CI 0.61-0.82], 4 trials, n=1638). Incidence of grade III/IV infections was significantly higher in patients receiving treatment with purine antagonists (RR 1.83 [95% 1.30-2.58], 4 trials, n=1620). There was no significant difference concerning the relative risk for grade III/IV neutropenia (RR 1.14 [95% CI 0.98-1.34], 4 trials, n=1620) and therapy-related mortality (RR 0.94 [95% CI 0.45-1.95]). Overall incidence of hemolytic anemia was low, but significantly increased in the purine antagonist group (RR 3.36 [95% CI 1.27-8.91], 3 trials, n=1258). AUTHORS' CONCLUSIONS: Despite significantly increased overall response and complete remission rates and longer progression-free survival with first-line treatment of B-CLL patients with single-agent purine antagonists, we were not able to detect a statistically significant improvement of overall survival compared to alkylator-based regimens. Furthermore, the use of purine antagonists also augments the risk for grade III/IV infections and hemolytic anemia.

Telomere length and telomerase activity predict survival in patients with B cell chronic lymphocytic leukemia.

The telomere-telomerase hypothesis states that the vast majority of human tumors have a prolonged replicative life span throughout expressing telomerase, which compensates the cell division-associated loss of telomere DNA. The use of telomere length and telomerase expression as new biological markers in cancer patients requires their correlation with disease prognosis. We, therefore, correlated the mean telomere length based on a telomere restriction fragment assay and the activity of telomerase measured with a telomeric repeat amplification protocol with clinical data and overall survival in 58 patients with B cell chronic lymphocytic leukemia (B-CLL). Telomere length showed a highly inverse correlation to telomerase activity. Patients with telomeres below 6.0 kb were associated with high telomerase activity, whereas patients with a telomere length >6.0 kb generally showed low enzyme activity (P <0.001). Patients in Binet A exhibited significantly longer telomeres and had less telomerase activity than did patients in Binet B or Binet C, where significantly shorter telomeres and higher telomerase activity were observed (P=0.031). Short telomere length and high telomerase activity were significantly associated with a shorter median survival (P=0.02 and P <0.001), and telomerase activity was the most significant prognostic factor for overall survival in B-CLL (P <0.001). Our data provide evidence that telomere length, as well telomerase activity, exerts a strong impact on the survival of B-CLL patients and that telomerase activity can be used as a new prognostic marker in this disease.

Multidrug resistance in acute leukemia: a comparison of different diagnostic methods.

Accurate measurement of P-glycoprotein (P-170) expression in clinical samples still remains a controversial issue. In this study tumor cell P-170 expression was assessed in 29 patients suffering from acute leukemia (17 acute myeloid leukemia (AML) and 12 acute lymphoblastic leukemia (ALL)) using three different techniques: flow cytometry measuring rhodamine 123 (Rh123) efflux (functional level), immunocytochemistry (protein level) and RT-PCR (mRNA level). Rh123 efflux was detectable in 10/29 (34%) of all cases, in 9/17 (53%) of AML and in 1/12 (8%) of ALL samples. In AML patients a significant association of CD34 expression and P-170 activity was observed (P < 0.02). All AML patients with the FAB subtype M5 were Rh123 negative (P < 0.007). Cytospin preparations were analyzed for staining with monoclonal antibodies JSB1 and MM4.17. Eight of 16 (50%) AML and 0/9 (0%) ALL cases expressed the multidrug resistance (MDR) protein assessed by JSB1. With MM4.17 87% of AML and 50% of ALL patients were scored positive. Agreement between both antibodies was found in only 13/23 (57%) samples. Extracted RNA from 12 patients was analyzed by RT-PCR to evaluate the expression of MDR1 and multidrug resistance-associated protein (MRP) mRNA. An increased level of MDR1 mRNA was detectable in 4/7 AML and 0/5 ALL cases. MRP expression was found in 3/7 AML and 0/5 ALL patients. Comparison of Rh123 assay and immunocytochemistry revealed a very good correlation when using MoAb JSB1 (P < 0.004) but not with MM4.17 (not significant (NS)). JSB1 also showed a much better association with the PCR results (P < 0.05) than MM4.17 (NS). Finally, we compared the results of the functional Rh123 assay and RT-PCR and observed a high correlation for Rh123/MDR1 (r = 0.819, P < 0.001) but low for Rh123/MRP (r = 0.562, NS). We conclude that measurement of Rh123 efflux and immunocytochemical staining of cytospin preparations with JSB1 allows the accurate monitoring of P-170 expression in acute leukemia. The simplicity of these two MDR assays suggests their use for routine MDR screening.

Transplantation of IL-2-transduced murine bone marrow is associated with dose-dependent toxicity.

OBJECTIVE: The purpose of this study was to investigate the effects of interleukin-2 (IL-2) gene-transduced hematopoietic progenitor cells or cytotoxic function and systemic toxicity following syngeneic bone marrow transplantation. MATERIAL AND METHODS: Marrow of 5-fluorouracil pretreated donor mice were transfected with a retroviral vector containing the murine IL-2 gene and transplanted into lethally irradiated syngeneic hosts. RESULTS: Productive insertion of the IL-2 gene could be demonstrated at various intervals post-transplant without impairment of hematopoietic engraftment. Endogenously augmented IL-2 release resulted in a selective increase in CD4(+), CD8(+), and NK1.1(+) population in spleen and bone marrow, as well as significant cytolytic activity against syngeneic leukemia cells in vitro. Our results also illustrate the interdependence among the magnitude of systemic IL-2 levels, the number of IL-2-transduced cells in the transplant inoculum, and the appearance of systemic toxicity. Infusion of marrow transduced with high-titer, high-expressing IL-2 retrovirus resulted in significant morbidity and mortality in the recipients. Our studies demonstrate that mortality was secondary to severe lymphocytic infiltration of liver and lung, which was associated with increased expression of intercellular adhesion molecule-1 and vascular adhesion molecule-1. Reducing the number of IL-2-transduced cells in the bone marrow inoculum, however, resulted in significantly improved survival with no adverse events being evident during the post-transplant period. CONCLUSION: Delivery of IL-2 to the bone marrow can be achieved by transplantation of genetically modified hematopoietic cells, however, the overall feasibility is strongly influenced by the number of transduced cells in the bone marrow inocolum and/or the expression pattern of IL-2 in vivo.

[Treatment of patients with radioiodine refractory, differentiated thyroid carcinoma. A Consensus Statement]. / Therapie des Patienten mit Radioiod-refraktärem, differenziertem Schilddrüsenkarzinom. Ein Konsensusstatement.

There is no clear standard therapy for patients with radioactive iodine (131I)-refractory locally advanced or metastatic differentiated thyroid cancer. The therapeutic options for this indication have expanded with the recently approved multiple kinase inhibitor sorafenib. Recommendations for the definition and the management of iodine refractory patients were worked up by an interdisciplinary expert panel, consisting of endocrine surgeons, medical oncologists and nuclear medicine specialists.

Expression of LFA-1 identifies different prognostic subgroups in patients with advanced follicle center lymphoma (FCL).

In a retrospective immunohistochemical study based on 27 patients with stage IV follicle center lymphoma (FCL) the expression of CD44standard (CD44s), LFA-1 (CD11a, CD18), VLA-4 (CD49d, CD29) and ICAM-1 (CD54) was analysed on lymphoma cells in bone marrow infiltrates. The results were correlated to clinical data and overall survival. Our data demonstrate that the expression of LFA-1 on lymphoma cells is predictive for the prognosis of patients with advanced FCL. In detail, patients exhibiting weak to moderate expression (+/++) of CD11 and CD18 showed a significantly shorter median survival (51 months and 33 months, respectively) than did those presenting with strong expression ( ) of the LFA-1 adhesion molecule (P = 0.04 and P = 0.0051, respectively). Furthermore, multivariate analysis identified CD18 as a new independent prognostic factor in patients with advanced FCL. Our findings emphasize the relevance of adhesion molecules for the pathology of FCL and give further support for their impact on clinical course and overall survival.

Characterisation of an echovirus type 11' (prime) epidemic strain causing haemorrhagic syndrome in newborn babies in Hungary.

Echovirus 11' (prime) isolates from an epidemic of haemorrhagic syndrome in departments of obstetrics in Hungary have been characterised. The leading component of the clinical disease was carditis and its lethal outcome occurred in 13 newborn babies. Maternal immunity was found to be absent even in women of 41 years of age. The application of monovalent oral poliovirus type 1 vaccine prevented the progress of the epidemic within two weeks. Nevertheless, a serological survey among primovacinees of 3-15 months of age revealed that 20% of the babies seroconverted without clinical symptoms during the epidemic. Serological evidence showed that the echovirus 11' infection was unable to interfere with the efficacy of oral poliovirus vaccine (OPV), since seroconversion rates of primovaccinees did not differ significantly from those in the group seroconverted also to echovirus 11' during the vaccination campaign. A 440 nucleotide (nt) fragment of the 5'-non-translated region of 12 epidemic echovirus 11' isolates and 26 echovirus prototype strains was amplified by a nested reverse transcription-polymerase chain reaction (RT-PCR) and analysed using three different restriction endonucleases. The 5'-regions of the echovirus 11' isolates were found to be identical to each other but different from that of the prototype echovirus 11 (Gregory) strain. The results indicate that echovirus 11' isolates underwent genetic changes in the 5'-end and P1 region of the genome before the onset of the epidemic.

[Information data on the incidence of nosocomial infections in Hungary]. / Tájékoztató adatok a nosocomialis fertözések hazai elöfordulásáról.

Authors registered the occurrence of nosocomial infections in altogether 1000, randomly selected case records at the surgical, gynecological, urological and intensive care wards of four county hospitals plus one large hospital in the capital in 1988. They found the proof of a total of 117 nosocomial infections occurring in 100 case records. The three most common infections in diminishing order were: urogenital-, wound- and respiratory infections. Twenty three infected patients developed sepsis, with a fatal outcome in every second among them. A nosocomial infection extended the period of hospital treatment in average by a week. In more than half of the cases microbiological examination for detecting the causative agent failed. Four fifth of the isolated bacteria were Gram-negative. Presented data of informatory nature suggest more decades arrearagement compared to the highly-developed countries.

[Management of gas gangrene in Hungary during 1979-1988 based on data from Public Health Centers]. / A gázgangréna kezelése Magyarországon 1979-1988-ban a KOJAL-ok adatai alapján.

Authors present data on the therapy of 223 gas gangrene cases between 1979-1988, a ten years period, based on the reports of Public Health Stations in Hungary. Of the 223 patients 150 died, thus lethality was 67.3%. In lack of surgical intervention there was no chance of survive. Merely wound exposure resulted in a much higher fatality rate than necrectomy of the wound. Local hydrogen-hyperoxide treatment improved survival essentially. Specific antitoxin therapy did not influence the survival rate. The effect of a single antibiotic was poor; combined antibiotic treatment gave a significantly better result. As for combination, the most effective were erythromycin, the lincosamids and chloramphenicol. According to the data presented, it would be possible to reduce to the half the fatality rate of gas gangrene in Hungary.

[Gas gangrene cases in Hungary 1979-1986]. / Gázgangraena megbetegedések Magyarországon 1979-1986-ban.

The authors evaluate epidemiologic data of 182 patients suffering from gas gangrene during an eight year period from 1979 to 1986. Of the patients surveyed 127 died; thus lethality reached 69.2%. The average age of the survivors was 49.9 year as opposed to the 66.1 year of the fatal cases. More than half of the illnesses followed amputation of extremities, and a quarter of them was a consequence of an accident. Samples of the bacteriologically examined wound discharges yielded in 93.1% bacteria from the Clostridium genus. Hygiene was poor in operation theatres and in the hospital environment in 1/4-th of the cases. Sixty six patients died within 24 hours after diagnosis. The presented data suggest that in Hungary the number of gas gangrene cases and deaths surpass those of tetanus.

[Incidence of post-transfusion hepatitis in Hungary 1987-1993]. / Posttransfusiós hepatitisek elöfordulása magyarországon 1987-töl 1993-ig.

The authors describe the epidemiological characteristics of hepatitis cases occurred after administration of blood or blood-preparations in Hungary, based on data collected between January 1987 and December 1993. The epidemiologists of the public health network reported 868 acute posttransfusion hepatitis within this seven years period. The number of the cases decreased year by year, and in accordance with the rapid development of virological diagnostics the rate of cases with uncovered aetiology increased gradually. Nevertheless the aetiology of more than half of the reported cases (466 patients, i.e. 53.6%) remained unknown. The results of the examinations were negative in 167 cases (19.2%), and no etiological examinations were carried out in 299 cases (34.4%). Hepatitis A was reported in 17 cases (2%), hepatitis B in 129 cases (14.9%), whilst non-A, non-B hepatitis was diagnosed in 188 cases based on examinations with an experimental NANB antigen and antibody tests or by exclusion of hepatitis A and B infectious (21.7%); from 1991 67 cases (7.7%) were diagnosed by standard tests as hepatitis C, and Epstein-Barr virus infection was reported in 1 case (0.1%). During the seven years 11 patients of the 868 (1.3%) died in the acute phase of the illness.

Small steps of improvement in small-cell lung cancer (SCLC) within two decades: a comprehensive analysis of 484 patients.

BACKGROUND: It is not clear whether or not the fate of patients suffering from small-cell lung cancer (SCLC) has improved. To better understand the course of disease, we aimed at documenting disease features at initial diagnosis, sequences of therapy modalities and outcome in consecutive patients over two decades. We postulated that SCLC patients might have benefitted from refined diagnosis and treatment options during the last decade. METHODS: All SCLC cases diagnosed at the Innsbruck University Hospital and associated institutions between 1991 and 2011 have been documented in detail in accordance with a prespecified protocol. RESULTS: A total of 484 patients diagnosed with SCLC were followed. The most important symptoms at initial diagnosis were cough, dyspnea and tumor pain in 55%, 51% and 44%, respectively. Patients who were operated during early stage of disease (n = 26) had a favorable 5-year, relapse-free survival (74%). A total of 112 patients with locally advanced disease were treated by radiochemotherapy in curative intent (RCT), and achievement of CR offered a chance of long term overall survival (OS), reaching 44% after 10-years. In the palliative setting (median OS in 304 evaluable patients, 9.7 months), a therapeutic progress in the more recent decade could not be observed. Parameters independently associated with favorable OS were: response to therapy and prophylactic brain irradiation in patients with RCT; and response, age < 70 years and absence of LDH elevation in the palliative setting. CONCLUSIONS: In this comprehensive view on SCLC, the findings on symptomatology, comorbidity, and spectrum of treatments may help to better understand individual courses of the disease. Overall, modern medicine failed to translate into substantial benefit of SCLC patients, except in patients in locally advanced disease receiving multimodal therapy.

Exposure to retinoic acid before or after the onset of somitogenesis reveals separate effects on rhombomeric segmentation and 3' HoxB gene expression domains.

We have compared the relationship between the patterns of altered morphogenesis and of altered gene expression in mouse embryos exposed to excess retinoic acid (RA) (a) just before and (b) just after the onset of somitic segmentation (day 7.75 to day 8.25). Exposure to RA prior to the onset of somitic segmentation results in suppression of rhombomeric (but not somitic) segmentation, and conversion of the genetic identity of the whole preotic hindbrain to that of rhombomere 4. In contrast, exposure to RA at early somite stages results in near-normal rhombomeric segmentation; rhombomeric gene expression domains indicate that only rhombomere 2 has changed its genetic identity to that of rhombomere 4, the other preotic segments showing normal expression patterns for HoxB genes and Krox-20. The results indicate that RA has separable effects (1) on the genes mediating the process of rhombomeric segmentation per se, such as Krox-20, and (2) on the genes that influence the nature of the structures that subsequently develop from the individual rhombomeres, such as the Hox genes.

Differential activity of P-glycoprotein in normal blood lymphocyte subsets.

To better understand the phenomenon of P-glycoprotein (P-170) expression we investigated lymphocyte subpopulations for P-170 function in healthy volunteers. Studies were based on three-colour flow cytometry including the fluorescent probe rhodamine 123 (Rh123), which is transported by P-170. Marked Rh123 efflux was detected in CD8+ T lymphocytes with CD8+/CD45RA+ T cells (naive cells) showing significantly higher P-170 activity as compared with CD8+/CD45RA- cells (P<0.04). Vice versa, CD8+/CD45RO+ T cells (memory cells) demonstrated less P-170 activity than CD8+/CD45RO- cells (P<0.04). P-170 function was less prominent in CD4+ T cells, however, Rh123 efflux was higher in the CD4+/CD45RA+ and CD4+/CD45RO- subpopulations (P<0.025) corresponding to the CD8+ results. Dye efflux differed significantly between activated and non-activated CD8+ and CD4+ as well as CD8+/CD11b+ and CD8+/CD11b- T lymphocytes. Since CD16+ natural killer cells (NK) expressed the highest level of P-170, the NK cytotoxicity against 51Cr-labelled K562 target cells was assayed in the presence or absence of P-170 inhibitors. NK related cytotoxicity was significantly reduced in the presence of R-verapamil and dexnigaldipine-HCP in a dose-dependent manner. The differential expression of P-170 activity in naive and memory T cells together with the reduced NK related cytotoxicity in the presence of MDR-modulators suggest a physiological role of P-170 in immunological functions of these lymphocyte subsets. Consequently, the addition of MDR modulators to conventional chemotherapy as a strategy to overcome drug resistance should consider possible adverse immunosuppressive effects.