Clinical outcome and global gene expression data support the existence of the estrogen receptor-negative/progesterone receptor-positive invasive breast cancer phenotype.

The presence or absence of estrogen and progesterone steroid hormone receptor expression (ER, PR) is an essential feature of invasive breast cancer and determines prognosis and endocrine treatment decisions. Among the four ER/PR receptor phenotypes, the ER-/PR+ is infrequent, and its clinical relevance has been controversially discussed. Thus, we investigated its clinical significance and gene expression pattern in large datasets. In a retrospective clinical study of 15,747 breast cancer patients, we determined the ER/PR subtype survival probabilities using Kaplan-Meier and Cox regression analyses. From The Cancer Genome Atlas (TCGA) breast cancer dataset, PAM50 expression signature and pathway analyses were performed to test for distinct molecular features. In our cohort, the ER-/PR+ phenotype has been observed at a frequency of 4.1 % and was associated with an improved 10-year survival for stage I cancers compared to the ER+/PR+ reference subtype (median; 95 % CI 88.1 %; 83-93 vs. 84.3 %; 82-86 %, P = 0.024) as was confirmed by multivariate analysis over the entire follow-up (HR 0.59, 95 % CI 0.38-0.92, P = 0.021). This association lacked significance when including all stages. ER-/PR+ patients treated with antihormonal agents (34.5 %) had shorter survival compared to their non-treated counterparts (Log-rank P = 0.0001). PAM50 signatures suggest a distinct configuration for the ER-/PR+ phenotype. This specific phenotype has been further separated by a set of 59 uniquely expressed genes. Our study supports the notion of the existence of an ER-/PR+ phenotype with clinical and molecular features distinct from the large group of ER+/PR+ patients.

[Cystic gastric tumor with calcifications]. / Zystischer Magentumor mit Verkalkungen.

In imaging techniques was seen a thickness of the gastric wall in a patient with pain for several months and loss of weight. Biopsies taken out of the tumor mass by gastroscopy and laparoscopy have not been ground-breaking. For this disease pattern is it not unusual that the diagnosis of heterotopic pancreatic tissue with pancreatitis is not confirmed until a resection of the stomach.

Cyclic alternating chemotherapy of high-grade malignant non-Hodgkin lymphomas with VIM-Bleo and CHOP.

Between 1986 and 1988, 81 patients with high grade malignant non-Hodgkin lymphoma according to the Kiel classification were treated with the VIM-Bleo/CHOP-regimen: etoposide 100 mg/m2 intravenously on days 1-3, ifosfamide 1.5 g/m2 intravenously days 1-5 with mesna for prophylaxis of cystitis, methotrexate 30 mg/m2 intravenously on days 3, bleomycin 10 mg intravenously on days 8 and 15, cyclophosphamide 750 mg/m2 day 22, doxorubicin 50 mg/m2 day 22, vincristine 1.4 mg/m2 on day 22, and prednisolone 100 mg postoperatively on days 1-5 and 22-26. Cycles were repeated four times beginning on day 43. Regions with bulky disease were irradiated after chemotherapy. 36 patients (44%) had stage II, 12 (15%) stage III and 33 (41%) stage IV disease. B-symptoms were present in 49% of patients. Serum lactate dehydrogenase activity was elevated in 53%. Overall, 59 patients (73%) achieved a complete and 14 (17%) a partial remission. 8 (9%) had stable or progressive disease. After a median follow up of 30 months thus far, probability of long-term relapse free survival is 66% for patients in complete remission. Overall survival is 72% at 24 months. Toxicity from treatment was very low with leukopenia being the main side effect. Major infections were observed in only 2% of cycles with one treatment related death. VIM-Bleo/CHOP is a well tolerated regimen with remission rates in the range of other, more toxic regimens. However, cyclic alternating treatment did not improve results as compared with repeated treatment with a single standard protocol.

Primary breast cancer therapy in six regions of Germany.

Studies from six regions of Germany (Aachen (W1), Dresden (E1), Jena (E2), Marburg (W2), Munich (W3), and Stuttgart (C1)) have been compared to verify and assess the quality of healthcare using breast cancer as an example. All of the data collection was carried out in comprehensive cancer centres and is population-based, with the exception of C1. Classic prognostic factors and the initial treatment of 8661 women with breast cancer, diagnosed between 1996 and 1998, were examined. Primary therapy, breast conserving therapy (BCT), and the use of subsequent local radiation and/or systemic therapy (chemotherapy or hormonal therapy) were analysed. BCT was performed on 39.3-57.7% of patients. By pT-category, the proportion of BCT in the six regions were as follows: for pTis between 37.8 and 64.3%, for pT1 between 51.7 and 71.5%, for pT2 between 25.9 and 51.1%, for pT3 between 0 and 13.1% and for pT4 between 0 and 15.2%. Multivariate analyses, adjusted for age and biological factors, showed a significant influence of the treating hospital on the mastectomy rate. The use of radiotherapy after BCT (80%) was quite homogeneous in the six regions. The application of radiotherapy after mastectomy, however, varied between 10.4 and 32.2%. In all regions, for premenopausal patients, the use of adjuvant systemic therapy almost reflected the St. Gallen-Consensus recommendations. In contrast, post-menopausal women with positive lymph nodes were not always treated according to these standards. In all regions, age had an influence on the administration of treatment: elderly breast cancer patients received less BCT, less radiotherapy and less adjuvant therapy than recommended in the St. Gallen-Consensus. Feedback of the results was made available to each hospital, providing a comparative summary of patient care that could be used by the participating hospitals for self-assessment and quality-control.

Comparative in vitro toxicity of mitoxantrone and adriamycin in human granulocyte-macrophage progenitor cells.

Mitoxantrone (MIT) has recently been introduced into cancer therapy as a possible substitute for the structurally related drug, adriamycin (ADR), because it causes less cardiotoxicity and fewer gastrointestinal side effects. However, the dose-limiting toxicity of MIT is pronounced neutropenia. The in vitro hematoxicity of both drugs in granulocyte-macrophage precursor cells (GM-CFCs) was analyzed using drug-exposure schedules analogous to the principles of the in vivo pharmacokinetics of MIT. Bone-marrow and peripheral-blood cells were exposed to 0.075-20 ng/ml MIT or ADR for 5, 20, 60, and 120 min, and for 14 days. The 14-day exposure resulted in Do values of 0.95 and 0.68 ng/ml for bone-marrow and peripheral-blood GM-CFCs subjected to MIT. Exposure to ADR resulted in Do values of 5.43 and 5.13 ng/ml, respectively. As was the case after 14-day exposure to MIT or ADR, short-term exposure again revealed that peripheral-blood GM-CFCs were more sensitive to both drugs. Moreover, at low concentrations, ADR was less toxic than MIT in both types of GM-CFCs, but was more toxic than MIT when a concentration of 20 ng/ml was used. The intracellular concentration of MIT, as measured by high-performance liquid chromatography, was constantly below 1 ng per 2 X 10(7) cells, even when it was applied at a concentration of 20 ng/ml for an exposure time of 2 h. The fact that such low concentrations of MIT are toxic for hemopoietic precursor cells may explain the myelotoxicity of this drug. However, the difference between the precursor-cell toxicity of MIT and that of ADR was small when their respective therapeutic doses were taken into consideration. Further analyses of their toxicity in stem cells and/or the microenvironment would appear to be needed.

Hospital accreditation and the surgeon: the Canadian experience.

Accreditation is an internationally recognised process through which healthcare organisations are able to improve the safety and quality of services delivered to patients. The focus of accreditation is to help organisations understand what they are doing well and what opportunities are available for improvement. The Canadian approach to accreditation is a rigorous peer review process comprised of a self-assessment against a set of standards, an on-site survey and follow-up action on recommendations that arise from the survey. The accreditation standards can be used effectively to guide the surgical teams in the transformation of the specialty. The 17 standards that are used to evaluate surgical teams relate to the activities that represent the continuum of clinical care as well as aspects related to learning. Within the subsections and standards are opportunities for surgeons and surgical teams to use the standards to effectively deliver services and to continuously improve patient care. In 38 recent Canadian Accreditation AIM surveys, that included at least one surgical team, there were a total of 75 recommendations made to the teams. Most recommendations related to process as opposed to outcome issues, implying that surgeons need to become more proactive in the functioning of the surgical team and to participate more effectively in management issues related to surgical care. Attention to these details will position surgical programmes to effectively deal with the rapid pace of change that is inherent in a modern surgical practice.

[Ischemic colitis as a primary manifestation of an embolizing small-cell bronchial carcinoma infiltrating a pulmonary vein]. / Ischämische Kolitis als Primärmanifestation eines in eine Pulmonalvene eingewachsenen, embolisierenden kleinzelligen Bronchialkarzinoms.

CASE REPORT: A 59-year-old male patient was admitted to hospital for general malaise with muscle and bone pain. Some weeks ago he had been treated with roxithromycin because of pneumonia. Physical examination revealed melena. Hemoglobin was 7.6 g/l. Endoscopy of the upper gastrointestinal tract did not show a bleeding source. Colonoscopy and histologic examination revealed hemorrhage caused by ischemic colitis. To rule out cardiac embolies in the presence of paroxysmal tachyarrhythmia absoluta a transesophageal echocardiogram was performed. A mediastinal mass infiltrating the upper left pulmonary vein was detected. The mass had not been visible on routine chest X-ray. Histologic examination of a bronchoscopically taken specimen revealed an oat-cell bronchial carcinoma. CONCLUSION: In this patient invasion of a pulmonary vein by the bronchial carcinoma lead to embolies which caused mesenterial ischemia. According to our researches this is the first report of ischemic colitis as a manifestation of bronchial carcinoma.

[Patella dislocation. Therapeutic principles and prevention of late complications]. / Patellaluksation. Behandlingsprincipper og forebyggelse af senkomplikationer.

In this review we have compared the different kinds of treatment of acute dislocation of the patella regarding the effects and the complications. The literature describes a variety of treatments and no standard treatment exists. Most studies are not randomised prospective studies and the follow-up period is often short. We conclude that there is a need for randomised, prospective studies with a large number of patients and with a long follow-up period in order to find the best kind of treatment. Treatment modalities for acute as well as recurrent dislocation are described in the general section of the review. In order to achieve the best results and decrease the number of complications it is necessary to have a clear diagnosis of APD and knowledge of predisposing factors.

[Acute and chronic patella dislocations. Therapeutic strategies in Danish orthopedic departments]. / Akutte og kroniske patellaluksationer. Behandlingsstrategier på danske ortopaedkirurgiske afdelinger.

BACKGROUND: In review of the literature there is no standard treatment of acute- as well as recurrent dislocation of the patella. Most investigations are retrospective or not randomised. Approximately 1500 patients/year with the diagnosis luxatio patellae are seen in Danish hospitals. METHODS: Using a questionnaire we wished to find out how these patients were treated in Danish orthopaedic departments. RESULTS: We found that there was no consensus on the treatment of patellar dislocation. CONCLUSION: We concluded that there is a need for prospective randomised studies involving a large number of patients, with a long follow up time.

[Symptom-oriented follow-up of early breast cancer compared to intensive surveillance. Results of a prospective multicentre study: update and 10-year overall survival]. / Symptomorientierte Nachsorge nach Mammakarzinom im Vergleich zur intensiv-apparativen Nachsorge. Ergebnisse einer prospektiven multizentrischen Studie: Update und 10-Jahres-Überlebenszeit.

BACKGROUND AND OBJECTIVE: In a prospective, non-randomised, multicentre cohort study we compared intensive surveillance to symptom-oriented control in the follow-up of patients with early breast cancer after curative surgical treatment. Five-year overall survival had shown that symptom-oriented follow-up was not inferior to intensive control. However, a more intensive, instrumental based follow-up is still claimed by many patients and their physicians. In this context the recent data of 10-year overall survival (OS) are reported. PATIENTS AND METHODS: In the prospective, non-randomised, multicentre cohort study carried out between 1995 and 2000, 244 patients underwent an intensive follow-up (scheduled laboratory tests including CEA and CA 15-3, chest X-rays and liver ultrasound). 426 patients were monitored in a symptom-oriented manner (additional tests only in the case of symptoms indicating possible recurrence). Mammography, structured histories and physical examinations were done regularly in both groups. RESULTS: In the clinical follow-up group, 90 deaths (21.2 %) were observed with an estimated 10-year overall survival rate of 83.0 % (95 % CI 79.1 -86.3 %).  In the intensive follow-up group, 59 deaths (24.2 %) were observed with an estimated 10-year overall survival rate of 78.5 % (95 % CI 72.6 -83.2 %). The Cox proportional hazards model for OS includes the variables follow-up form, stage of primary tumor and lymph nodes, hormone receptor status, grading and age at diagnosis. This model resulted in a hazard ratio of 1.10 (95 % CI 0.78-1.54) for the follow-up protocol (intensive vs. clinical). Welleks' test for non-inferiority showed that clinical follow-up is not inferior in comparison to intensive follow-up (p < 0.05) for a non-inferiority limit of + 7 % at 10-years. CONCLUSION: This analysis of 10-year overall survival of patients with early breast cancer after curative primary treatment confirms that follow-up without regular imaging and laboratory tests is not inferior in the sense of a relevant higher mortality. To what extent new concepts in the treatment of breast cancer have any influence on follow-up care has to be examined in further studies.

Clinical impacts of histological subtyping primary breast cancer.

BACKGROUND: Treatment decisions in breast cancer depend on TNM classification and the assessment of additional variables with have an impact on survival. We examined whether histological subtyping breast cancer as either ductal or lobular is related to disease outcome. PATIENTS AND METHODS: We examined a large data base of 14198 breast cancer patients. RESULTS: Histological sub-classification of invasive breast cancer as either ductal or lobular is not correlated with disease outcome. However, the data further showed that invasive lobular carcinomas have a higher probability of being oestrogen receptor (ER)- and progesterone receptor (PR)-positive and a lower probability of being c-erbB2-positive. They also showed a higher average age at the time of diagnosis in comparison with invasive ductal carcinoma. Local recurrence rates were lower in invasive lobular carcinoma in comparison with invasive ductal carcinoma (3.5% vs. 6.2%; p = 0.031). The multivariable Cox regression analysis showed that ER, PR, nodal status, grade and tumour size predicted disease outcome with statistical significance, while the histological subtype (invasive ductal or lobular) was not a significant predictor of disease outcome. CONCLUSION: Histological sub-classification of invasive breast cancer as either ductal or lobular is not correlated with disease outcome. On the other hand our data gives some indication that lobular and ductal breast cancer appear to be different biological entities.

[Humoral factors in the regulation of cell proliferation in haematopoiesis. I. Granulopoiesis and lymphopoiesis (author's transl)]. / Humorale Regulatoren der Zellproliferation in der hämatopoese. I. Granulopoese und Lymphopoese.

Humoral Factors obviously play an important role in the maintenance of the steady state in haematopoiesis. There has been work on stimulators and inhibitors for several years. Colony-stimulating factor is the best characterized chemically and biologically. Interest in more or less cell-line-specific stimulators and inhibitors of lymphopoiesis is now growing. Various tissue extracts and cell culture supernatants have been partially purified and characterized biologically and chemically. Monocytes, producing stimulators and inhibitors, have a central function in the regulation of cell proliferation in haematopoiesis. Experiments performed in vitro can help better to understand data so far difficult to explain regarding patients with disturbed haematopoiesis. The in vivo relevance of these experiments, however, remains unclear.

[Humoral factors in the regulation of cell proliferation in haematopoiesis. II. Erythropoiesis, megakaryopoiesis, multipotent stem cell (author's transl)]. / Humorale regulatoren der Zellproliferation in der Hämatopoese. II. Erythropoese, Megakaryopoese, pluripotente Stammzelle.

Diffusible factors probably play an important role in the control of cell proliferation during haematopoiesis. Several stimulators of erythropoiesis including erythropoietin are to be found in sera. Inhibitors are found in erythrocyte supernatants, in the urin of newborn children, and in plasma of patients with renal insufficiency. Stimulators of megakaryopoiesis have been shown to be present in conditioned media of lymphoid cells and bone marrow cells. Inhibitors have been detected in various sera. Proliferation of multipotent stem cells is probably also regulated by a humoral mechanism. Stimulators and inhibitors are present in bone marrow extracts. Clinical relevance of these factors is discussed.

[What do we know about the prevalence of pain caused by malignancy?]. / Tumorpatienten in Deutschland: Was wissen wir über Schmerzprävalenzen?

BACKGROUND: Since there is no epidemiologic assessment of the frequency of pain caused by tumor in Germany, tumor-pain-prevalence is estimated indirectly on the basis of mortality and median survival. Knowing that about 50% of all patients having metastases or incurable locoregional recurrence suffer from pain every day, the product of median survival times mortality was calculated to achieve the number of patients' days with tumor-caused pain per year (82,710,690 days in Germany 1995). By division with 365 (days), it is calculated that 226,605 patients require tumor pain related treatment at one day in Germany. Another calculation based on Bonica's publications that 60-90% of patients suffering from advanced cancer are having pain and based on an estimated tumor prevalence 1989/90 revealed a tumor pain prevalence of 221,826. DISCUSSION: Thus both methods result in the estimation, that about 220,000 patients require tumor-pain-related treatment at one day in Germany.

[Therapeutic aspects of advanced high risk breast cancer]. / Therapeutische Aspekte des fortgeschrittenen Hochrisiko-Mammakarzinoms.

In the treatment of metastatic breast cancer patients, remission rates and survival are determined by prognostic criteria and not by the choice of treatment. It remains to be proven whether or not the intensification of chemotherapy leads to a higher complete remission rate and/or prolongs survival. Generally, patients derive benefit from achieving a "no change" status. Therefore, milder treatment regimens are preferred except in clinical trials. However, additional research is mandatory to analyze treatment results in clearly defined prognostic subgroups to determine if specific subgroups benefit with prolonged survival and/or improved quality of life. Aggressive treatment with severe side effects should only be administered in such studies or if milder treatment regimes are no longer effective. The aim of palliation has to be kept in mind.