Complexity of patients with or without infectious disease consultation in tertiary-care hospitals in Germany.

PURPOSE: Patients seen by infectious disease (ID) specialists are more complex compared to patients treated by other subspecialities according to Tonelli et al. (2018). However, larger studies on the complexity of patients related to the involvement of ID consultation services are missing. METHODS: Data of patients being treated in 2015 and 2019 in four different German university hospitals was retrospectively collected. Data were collected from the hospitals' software system and included whether the patients received an ID consultation as well as patient clinical complexity level (PCCL), case mix index (CMI) and length of stay (LOS) as a measurement for the patients' complexity. Furthermore, a comparison of patients with distinct infectious diseases treated with or without an ID consultation was initiated. RESULTS: In total, 215.915 patients were included in the study, 3% (n = 6311) of those were seen by an ID consultant. Patients receiving ID consultations had a significantly (p < 0.05) higher PCCL (median 4 vs. 0), CMI (median 3,8 vs. 1,1) and deviation of the expected mean LOS (median 7 days vs. 0 days) than patients in the control group. No differences among hospitals or between years were observed. Comparing patients with distinct infectious diseases treated with or without an ID consultation, the differences were confirmed throughout the groups. CONCLUSION: Patients receiving ID consultations are highly complex, frequently need further treatment after discharge and have a high economic impact. Thus, ID specialists should be clinically trained in a broad spectrum of diseases and treating these complex patients should be sufficiently remunerated.

Economic burden of clinical trials in lung cancer in a German Comprehensive Cancer Center.

OBJECTIVES: The recent success of individualized lung cancer therapy has triggered fundamental changes in clinical research strategies. To date there is a strong focus on early proof of concept trials in genetically preselected small patient subgroups. This analysis focuses on the economic burden caused by such trials for advanced lung cancer patients in a German Comprehensive Cancer Center (CCC). METHODS: The profit margins between recruiting groups with ≤3 and >3 patients were compared. Clinical and economic data from clinical trials for advanced lung cancer (LC), pharma-sponsored trials (PhST) as well as investigator initiated trials (IIT), conducted between 2011 and 2015 at the Center for Integrated Oncology (CIO) Cologne, were analyzed using a profit-center calculation model. RESULTS: 161 patients were enrolled in 27 clinical trials. The key economic parameter determining costs and payments was the 'trial visits'. In comparison of the two groups (A≤3; B>3 patients enrolled) we found negative profit margins for the low recruiting group (€ -1444). Concerning the number of visits significant differences were found between PhST and IIT (p=0.009). Additionally, sub-analysis show structural differences in cost composition by conducting PhST and IIT. CONCLUSION: Trials with low patient numbers and IIT, do not cover the cost. To ensure adequate, cost-covering compensation by pharmaceutical companies CCCs have to thoroughly calculate the cost of early proof of concept trials. The findings of this study also underline the need for novel structures in public funding for investigator-initiated clinical trials in precision medicine.

Candidemia in the intensive care unit: analysis of direct treatment costs and clinical outcome in patients treated with echinocandins or fluconazole.

Direct treatment costs caused by candidemia in German intensive care unit (ICU) patients are currently unknown. We analyzed treatment costs and the impact of antifungal drug choice. Comprehensive data of patients who had at least one episode of candidemia while staying in the ICU between 01/2005 and 12/2010 were documented in a database using the technology of the Cologne Cohort of Neutropenic Patients (CoCoNut). A detailed analysis of all disease-associated treatment costs was performed. Patients treated with echinocandins (i.e., anidulafungin, caspofungin, micafungin) or fluconazole were analyzed separately and compared. Forty-one and 64 patients received echinocandins and fluconazole, respectively. The mean Acute Physiology and Chronic Health Evaluation (APACHE) IV score was 114 (95 % confidence interval [CI]: 106-122) vs. 95 (95 % CI: 90-101, p = <0.001). Twenty-three (56 %) and 33 (52 %, p = 0.448) patients survived hospitalization, while 17 (41 %) and 22 (34 %, p = 0.574) survived one year after diagnosis. In the echinocandin and fluconazole groups, the mean costs per patient of ICU treatment were 20,338 (95 % CI: 12,893-27,883) vs. 11,932 (95 % CI: 8,016-15,849, p = 0.110), and the total direct treatment costs per patient were 37,995 (95 % CI: 26,614-49,376) vs. 22,305 (95 % CI: 16,817-27,793, p = 0.012), resulting in daily costs per patient of 1,158 (95 % CI: 1,036-1,280) vs. 927 (95 % CI: 828-1,026, p = 0.001). Our health economic analysis shows the high treatment costs of patients with candidemia in the ICU. Sicker patients had a prolonged hospitalization and were more likely to receive echinocandins, leading to higher treatment costs. Outcomes were comparable to those achieved in less sick patients with fluconazole.

BEACOPP and COPP/ABVD as salvage treatment after primary extended field radiation therapy of early stage Hodgkins disease - results of the German Hodgkin Study Group.

Patients with early stage favorable Hodgkin's disease who relapse after extended field radiotherapy have satisfactory results. We retrospectively analysed patients with relapsed HD after initial radiation therapy alone to determine treatment outcome and prognostic factors. Nine-hundred and forty five patients in localized stages without risk factors received either 40 Gy extended field RT or 30 Gy EF RT followed by an additional 10 Gy to involved lymph node regions. 107 patients relapsed and received salvage therapy. Characteristics of the 107 patients at relapse were as follows: median age was 34 years (range 18--75) with relapse occuring at a median of 19 months (range 4--98 months), 31% were female. The majority of patients (93%) were treated with conventional chemotherapy. Sixty-nine percent were treated with COPP/ABVD like regimens, 21% with BEACOPP, and 3% received various other regimens. Seven percent were treated with radiotherapy alone. Complete remission was achieved in 87% of all salvaged patients. The median follow-up after relapse was 45 months. FF2F (freedom from second treatment failure) and OS (overall survival) were 81% and 89%, respectively. In multivariate analysis age was the major prognostic factor for FF2F and OS (p<0.0001, for both). Further independent prognostic factors were B symptoms (p=0.05) and salvage chemotherapy (p=0.03) for FF2F, and B symptoms (p=0.03) and extranodal involvement (p=0.02) for OS. The long-term outcome of patients relapsing after EF RT is excellent. Age, B symptoms, extranodal involvement and salvage chemotherapy were identified as prognostic factors for second relapse and survival.

High-dose sequential chemotherapy followed by autologous stem cell transplantation in relapsed and refractory aggressive non-Hodgkin's lymphoma: results of a multicenter phase II study.

BACKGROUND: Combination chemotherapy can cure patients with non-Hodgkin's lymphoma (NHL), but those who suffer treatment failure or relapse still have a poor prognosis. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) can improve the outcome of these patients. We evaluated an intensified high-dose sequential chemotherapy program with a final myeloablative course. PATIENTS AND METHODS: Inclusion criteria were age 18-65 years, histologically proven primary progressive or relapsed aggressive NHL and eligibility for HDCT. The therapy consists of two cycles DHAP: dexamethasone 40 mg (day 1-4), high-dose cytarabine 2 g/m2 12q (day 2), cisplatin 100 mg/m2 (day 51); patients with partial (PR) or complete remission (CR) received cyclophosphamide 4 g/m2 (day 37), followed by peripheral blood stem cell (PBSC) harvest; methotrexate 8 g/m2 (day 1) plus vincristine 1.4 mg/m2 (day 51); and etoposide 500 mg/m2 (day 58-62). The final myeloblative course was BEAM: cytarabine 200 mg/m2 12q (day 81-84), etoposide 150 mg/m2 12q (day 81-84), melphalan 140 mg/m2 (day 80), carmustin 300 mg/m2 (day 80) followed by PBSCT. RESULTS: Fifty-seven patients (median age 43 years, range 24-65) were enrolled: 23 (40%) patients were refractory to primary therapy and 34 (60%) patients had relapsed NHL. The response rate (RR) after 2 cycles of DHAP was 72% (9% CR, 63% PR) and at the final evaluation (100 days post transplantation) 43% (32% CR, 11% PR). Toxicity was tolerable. Median follow-up was 25 months (range 1-76 months). Freedom from second failure (FF2F) and overall survival (OS) at 2 years were 25% and 47% for all patients, respectively. FF2F at 2 years for patients with relapse and for patients refractory to primary therapy were 35% and 9% (P=0.0006), respectively. OS at 2 years for patients with relapse and for patients refractory to primary therapy were 58% and 24% (P=0.0044), respectively. CONCLUSIONS: We conclude that this regimen is feasible, tolerable and effective in patients with relapsed NHL. In contrast, the results in patients with progressive disease are unsatisfactory. This program is currently being modified by addition of rituximab for patients with relapsed aggressive NHL.

Cologne high-dose sequential chemotherapy in relapsed and refractory Hodgkin lymphoma: results of a large multicenter study of the German Hodgkin Lymphoma Study Group (GHSG).

BACKGROUND: We designed a dose- and time-intensified high-dose sequential chemotherapy regimen for patients with relapsed and refractory Hodgkin lymphoma (HD). PATIENTS AND METHODS: Eligibility criteria included age 18-65 years, histologically proven primary progressive (PD) or relapsed HD. Treatment consisted of two cycles DHAP (dexamethasone, high-dose cytarabine, cisplatinum); patients with chemosensitive disease received cyclophosphamide followed by peripheral blood stem cell harvest; methotrexate plus vincristine, etoposide and BEAM plus peripheral blood stem cell transplantation (PBSCT). RESULTS: A total of 102 patients (median age 34 years, range 18-64) were enrolled. The response rate was 80% (72% complete response, 8% partial response). With a median follow-up of 30 months (range 3-61 months), freedom from second failure (FF2F) and overall survival (OS) were 59% and 78% for all patients, respectively. FF2F and OS for patients with early relapse were 62% and 81%, for late relapse 65% and 81%; for PD 41% and 48%, and for multiple relapse 39% and 48%, respectively. In multivariate analysis response after DHAP (P <0.0001) and duration of first remission (PD and multiple relapse versus early and late relapse; P=0.0127) were prognostic factors for FF2F. Response after DHAP (P <0.0081), duration of first remission (P=0.0017) and anemia (P=0.019) were significant for OS. CONCLUSION: Based on the promising results of this study, a prospective randomized European intergroup study was started comparing this intensified regimen with two courses of DHAP followed by BEAM (HD-R2 protocol).

Recombinant human erythropoietin, epoetin beta, in patients with relapsed lymphoma treated with aggressive sequential salvage chemotherapy--results of a randomized trial.

The aim of the study was to investigate the effects of erythropoietin (epoetin beta) on red blood cell (RBC) transfusions, hemoglobin (Hb) levels, and quality of life (QOL) in patients with relapsed lymphoma treated with an aggressive sequential salvage chemotherapy (SSCT) regimen. Sixty patients with early or late relapsed Hodgkin's disease ( n=39) or first relapse of aggressive non-Hodgkin's lymphoma ( n=21) were randomized to receive epoetin beta 10,000 IE subcutaneously three times a week or no epoetin during salvage chemotherapy. Patients in both study arms received two cycles of DHAP (dexamethasone, high-dose cytarabine, cisplatin); patients in partial remission (PR) or complete remission (CR) then received cyclophosphamide, followed by peripheral blood stem cell (PBSC) harvest, methotrexate plus vincristine, and etoposide. The final myeloablative course was BEAM (carmustine, etoposide, cytarabine, and melphalan) followed by autologous stem cell support. The primary endpoint of the study was the number of RBC units needed during SSCT. In addition, Hb levels and QOL were measured. The mean number of RBC units given in the epoetin beta arm was 4.5 compared to 8.3 in the control arm ( P=0.0134). The mean Hb levels during therapy were 10.4 g/dl in the epoetin beta arm and 9.7 g/dl in the control ( P=0.018). From baseline until BEAM therapy QOL (EORTC QLQ C30) and fatigue (MFI) assessment showed little QOL worsening or stable levels in both arms with a steeper increase of fatigue levels in the control group. Patients with relapsed lymphoma undergoing aggressive chemotherapy and stem cell support benefited from epoetin beta therapy, with a decrease of RBC transfusion requirements and lower rise of fatigue levels.

p21/waf1/cip1 in gastric cancer: associations with histopathological subtypes, lymphonodal metastasis, prognosis and p53 status.

BACKGROUND: Cyclins and cyclin-dependent kinases are determining factors of the cell cycle. In the present study, we investigated the role of p21 and p53 in the biology of gastric cancer, focusing on its influence on progression and prognosis (n = 195). METHODS: P21 and p53 immunoreactivity was analysed immunohistochemically, applying monoclonal antibodies. The p53 status was comparatively evaluated by PCR-SSCP analysis of p53 mutations in selected tumours. RESULTS: Fifty-eight percent of the carcinomas were p21+ in more than 5% of the cancer cell nuclei, whereas 19% exhibited a p21 immunoreactivity in more than 20% of the nuclei. On the other hand, p53 was over-expressed (in more than 50% of the nuclei) in about 45% of the specimens. P21 immunoreactivity in more than 5% of the nuclei was inversely related to the pN as well as pTNM cancer stage, whereas only a strong p21 expression (in >20% of the nuclei) was correlated with a better survival probability in a univariate analysis. The p53 status was associated with lymphonodal metastasis, but not with prognostic data. In multivariate survival analyses, neither p21 nor p53 emerged as independent prognostic factors. Compared with the results of p53 mutation analysis by PCR-SSCP. p21 immunoreactivity was reduced in p53-mutated cases. CONCLUSIONS: These features show an association of p21 over-expression with certain clinico-pathological parameters of gastric cancer. In this context, our data suggest that p21 immunoreactivity in more than 5% of the tumour cells has a predictive value for the course of adenocarcinoma of the stomach.

Immunoreactivity of monoclonal antibody BW835 represents a marker of progression and prognosis in early gastric cancer.

The Thomsen-Friedenreich (TF) antigen is a well-known human pan-carcinoma antigen. It represents a carbohydrate core disaccharide (Gal beta 1-3GalNAc) which is predominantly bound to mucin peptide cores. Its immunoreactivity depends on changes in glycosylation which lead to a reduction in the carbohydrate chain length and the exposure of core carbohydrates. In the present study, we investigated 208 gastric adenocarcinomas with respect to their immunohistochemical reactivity applying two monoclonal antibodies (MAbs). MAb specifically detecting TF antigen (A78-G/A7) and MAb BW835 were included. The latter reacts with a certain glycoform of the MUC1 peptide core, characterized by core-type glycans like TF. A78-G/A7 epitopes were detected in 68.8% and BW835 epitopes in 57.7% of the carcinomas. BW835 immunoreactivity correlated with the presence of lymph node metastases. Both A78-G/A7 and BW835 staining were significantly stronger in tubular/papillary cancer (WHO classification) and intestinal-type cancer according to Laurén. In univariate survival analyses of all patients studied, BW835 immunoreactivity was a marker of an unfavorable prognosis (p < 0.05). The presence of A78-G/A7 and BW835 epitopes exerted a negative effect on the subgroup of pTNM stage I carcinomas. These results indicate that TF and MUC1-TF immunoreactivity defines a 'high-risk' subgroup of stage I patients in gastric cancer.

["Lean management" in hospitals: potentials and limitations]. / "Lean Management" im ärztlichen Bereich. Möglichkeiten und Grenzen.

Little attention has yet been payed on establishing modern and competitive organizational structures in German hospitals. In this paper, we attempt to apply elements of lean management to the work of physicians working in an inpatient setting. Traditional ways of communication and their disadvantages are discussed. These include loss of motivation, bureaucratic structures and a lack of interdisciplinary cooperation. Using Maslow's theory of motivation, possible improvements are discussed, such as the reduction of restrictive job characteristics, an increase of physicians' spheres of competence and the use of their innovative potentials. These suggestions are explained using practical examples. The aim of the study is to contribute to quality management in hospitals by increasing personal responsibilities according to lean management.

Increased galectin-3 expression in gastric cancer: correlations with histopathological subtypes, galactosylated antigens and tumor cell proliferation.

Galectin-3 represents an endogenous galactoside-binding lectin which may be involved in tumor cell adhesion and proliferation. In order to evaluate its biological significance in human gastric cancer, we investigated its expression in the stomach of a large series of patients (n = 193) by immunohistochemical staining with the monoclonal antibody Mac-2. Compared to normal tissues, primary gastric adenocarcinomas showed a slight increase in galectin-3 expression. However, there was no correlation of membrane-bound and cytoplasmic galectin-3 with histopathological differentiation parameters (according to the WHO and Laurén classifications) or tumor progression (as documented by pTNM staging). Nuclear galectin-3 reactivity was significantly stronger in diffuse-type cancer compared to the intestinal-type tumors. Galectin-3 binds to terminal GalNAcalpha(1-3) bound to polylactosamine chains and related glycotopes. Therefore, the strong coexpression of membrane/cytoplasmic galectin-3 with Griffonia simplicifolia agglutinin I (GSA I) binding sites (Galalpha1-3Gal-, GalNAcalpha-) on carcinoma cells seems to be interesting. On the other hand, nuclear galectin-3 immunoreactivity did not correlate with the incidence of Ki-67-positive tumor cells. A prognostic value of galectin-3 regarding patient survival could not be established.

Can factors influencing in-patient treatment in Hodgkin's disease be identified?--Retrospective analysis of HD6 patients of the GHSG.

Patients receiving chemotherapy for Hodgkin's disease can potentially be treated in the out-patient department. In spite of this the proportion of patients receiving the chemotherapy on in-patient departments is 54% per chemotherapy cycle in average in the HD6 trial for advanced Hodgkin's disease of the German Hodgkin Study Group (GHSG). The aim of this retrospective analysis is to identify the set of parameters which influence the decision of in- or out-patient treatment for the patients in the HD6 trial. Parameters tested in the univariate analysis are the patient characteristics, the type of chemotherapy, toxicity and the type of treatment institution. The significant parameters are included in a logistic regression model. From this multivariate analysis the type of treatment institution turned out to be the most important factor in the decision of treatment setting. Restricting the analysis to university clinics, the treatment setting of the first two cycles is more influencial than patient dependent parameters.

Correlation of the immunohistochemical reactivity of mucin peptide cores MUC1 and MUC2 with the histopathological subtype and prognosis of gastric carcinomas.

The expression of MUC1 and MUC2 mucin peptide core antigens in gastric carcinomas was studied by immunohistochemistry to determine correlations with TNM stage and histo-pathological classifications as well as a possible prognostic impact. Paraffin-embedded specimens from 128 gastric carcinomas with a minimal follow-up of 5 years were immunostained. In addition to a polyclonal antiserum generated against polymorphic epithelial mucin (MUC1) from human milk, 2 monoclonal antibodies (MAbs), HMFG2 (anti-MUC1) and 4FI (anti-MUC2), were applied. Reactivity of carcinomas was correlated with the classifications of the UICC (TNM), WHO and Laurén. Correlations with overall survival were analyzed using the Kaplan and Meier product limit method. MUC1 immunoreactivity was associated with an advanced pTNM stage. The demonstration of both mucin species (MUC1, MUC2) displayed a statistically significant correlation with tubular/papillary vs. signet-ring cell differentiation as well as with intestinal-type vs. diffuse-type of tumor growth according to Laurén. In particular, MUC2 was only rarely detectable in signet-ring cell and diffuse-type tumors. MUC1 correlated with poor prognosis in all cases and the subgroup of stage I tumors. According to the histopathological classifications, a similar result was observed in signet-ring cell and diffuse-type carcinomas. In contrast, MUC2 reactivity was associated with a favourable prognosis of intestinal-type carcinomas. In the non-neoplastic gastric mucosa, both peptide cores were recognized in the superficial epithelium, whereas parietal cells contained only MUC1, and intestinal metaplasia almost exclusively MUC2 antigens. We conclude that the mucin peptide core antigens are suitable markers for the tubule-rich gastric carcinomas, which may in part be derived from intestinal metaplasia. In addition, MUC1 may exert a prognostic relevance and appears to be involved in the progression of diffuse-type tumors.