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G Köhler

Publications and source records attributed to G Köhler.

At least 73 records · Page 4Linked to original sources
PubMed1998

Successful treatment of gastrointestinal vasculitis due to systemic lupus erythematosus with intravenous pulse cyclophosphamide: a clinical case report and review of the literature.

Gastrointestinal vasculitis in systemic lupus erythematosus (SLE) is quite rare and almost always accompanied by evidence of active disease in other organs, although occasionally it may be the presenting feature of the disease. Gastrointestinal involvement in SLE may present as lupus peritonitis, non-necrotizing pancreatitis, gastrointestinal vasculitis or surgical abdomen. Here we report a severe case of SLE which presented initially with fever of unknown origin. Severe distress, abdominal pain, the presence of occult blood in the stool and high acute-phase proteins were explained by a lupus peritonitis and intestinal vasculitis resembling inflammatory bowel disease. Whereas high-dose prednisone treatment did not prevent a severe relapse, we observed a sustained remission following i.v. cyclophosphamide pulse therapy. In the literature, only two similar cases are reported: one died despite a change in the therapy of a bowel perforation; our case was the second that improved under pulse cyclophosphamide. We suggest the use of cyclophosphamide after failure of steroids early in the course of SLE gastrointestinal vasculitis to prevent devastating complications.

Abdominal Pain↗
PubMed1998

Interleukin-12 is essential for a protective Th1 response in mice infected with Cryptococcus neoformans.

To analyze the roles of interleukin-12 (IL-12) and the IL-12-dependent Th1 response in resistance to Cryptococcus neoformans, we have established a chronic infection model in wild-type mice and in mice with targeted disruptions of the genes for the IL-12p35 and IL-12p40 subunits (IL-12p35(-/-) and IL-12p40(-/-) mice, respectively) as well as in mice with a targeted disruption of the IL-4 gene. Long-term application of exogenous IL-12 prevented death of infected wild-type mice for the entire period of the experiment (up to 180 days) but did not resolve the infection. Infected IL-12p35(-/-) and IL-12p40(-/-) mice died significantly earlier than infected wild-type mice, whereas infection of IL-4-deficient mice led to prolonged survival. Interestingly, infected IL-12p40(-/-) mice died earlier and developed higher organ burdens than IL-12p35(-/-) mice, which, for the first time in an infection model, suggests a protective role of the IL-12p40 subunit independent of the IL-12 heterodimer. The fungal organ burdens of IL-4-deficient mice and IL-12-treated wild-type mice were significantly reduced compared to those of untreated wild-type mice and IL-12-deficient mice. Histopathological analysis revealed reduction of the number of granulomatous lesions following treatment with IL-12. Susceptibility of both IL-12p35(-/-) and IL-12p40(-/-) mice was associated with marginal production of gamma interferon and elevated levels of IL-4 from CD4(+) T cells, which indicates Th2 polarization in the absence of IL-12, whereas wild-type mice developed a Th1 response. Taken together, our data emphasize the essential role of IL-12 for protective Th1 responses against C. neoformans.

Animals↗
PubMed1998

Defective nitric oxide effector functions lead to extreme susceptibility of Trypanosoma cruzi-infected mice deficient in gamma interferon receptor or inducible nitric oxide synthase.

Trypanosoma cruzi, the causative agent of Chagas' disease, induces an innate and adaptive host immune response during the acute phase of infection. These responses were analyzed by comparing mouse lines deficient for the gamma interferon (IFN-gamma) receptor (IFN-gammaR(-/-)) or deficient for inducible nitric oxide synthase (iNOS(-/-)). Both lines were highly susceptible, with similar and dramatically increased parasite burdens and severe histopathology and were incapable of surviving even very low doses, exhibiting similar mortality kinetics. This pathophysiological correlation has a common cause, since both mutant mouse strains were unable to respond to infection by producing nitric oxide (NO) with the consequence that mutant macrophages had impaired trypanocidal activities. These in vivo and subsequent in vitro studies further demonstrated that an IFN-gamma-dependent pathway of iNOS induction is crucial for efficient NO production and mandatory for resisting acute infection with T. cruzi. Despite this defect, both mutant mouse strains had a rather normal proinflammatory cytokine response (interleukin-12 [IL-12], IFN-gamma, IL-6), with the exception of an impaired tumor necrosis factor alpha and IL-1alpha response in IFN-gammaR(-/-) mice, demonstrating that only the latter two cytokines are dependent on IFN-gamma activation. Moreover, polarization of T cells in type 1 and type 2 T-helper (Th1/Th2) and cytotoxic T (Tc1/Tc2) cells as well as T. cruzi-specific antibody responses were normal in IFN-gammaR(-/-) mice, demonstrating that IFN-gamma is not necessary for the promotion of T-cell differentiation and T. cruzi-specific antibody responses.

Animals↗
PubMed1998

Metastatic breast cancer: experience with the combination paclitaxel plus epirubicin.

This study evaluated the safety and feasibility of the combination of paclitaxel (Taxol) and epirubicin, the 4'-epimer of doxorubicin, in women with metastatic breast cancer. A total of 85 patients with histologically proven metastatic breast cancer were treated in two cohorts; epirubicin 60 mg/m2 i.v. infused over 1 hour, followed by paclitaxel 175 mg/m2 i.v. infused over 3 hours (group A), and epirubicin 90 mg/m2 i.v. via a 1-hour infusion, followed by paclitaxel 175 mg/m2 i.v. via a 3-hour infusion (group B). Of the 85 patients, 68 were evaluable for response and toxicity (43 in group A and 25 in group B). The combination was generally well tolerated. The higher epirubicin dose induced more severe neutropenia and one case of cardiotoxicity. Nonhematologic toxicities were mild, with no severe mucositis or peripheral neuropathy reported. Overall, 68% of patients in group A and 68% of patients in group B responded. A phase III trial comparing paclitaxel, 175 mg/m2, plus epirubicin, 60 mg/m2, with the standard combination of epirubicin, 60 mg/m2, and cyclophosphamide (Cytoxan, Neosar), 600 mg/m2, is currently in progress.

Antibiotics, Antineoplastic↗
PubMed1997

Annexin V interaction with phosphatidylserine-containing vesicles at low and neutral pH.

Annexin V belongs to a class of Ca2+-binding proteins for which different functions in the cell are discussed, e.g., involvement in exocytosis, inhibition of protein kinase C, and calcium channel activity in cartilage matrix vesicles. All these functions are related to the ability of the annexins to bind to acidic phospholipids. In this study, the interaction of annexin V with large unilamellar vesicles (LUV) prepared from phosphatidylserine (PS) at low pH was compared to that at neutral pH. Annexin V strongly binds to PS LUV at low pH, whereas at neutral pH 20-100 microM Ca2+ are required to induce binding. This is caused by the different electric charge of the protein. The binding ability of the PS LUV for annexin V is higher at low pH. Binding of annexin V induces dehydration of the vesicle surface and a decrease of the lateral diffusion within the bilayer. While this dehydration is due to vesicle contact at pH 4, at pH 7.4 it is due to surface covering by annexin V. Annexin V promotes the phospholipid intermixing between LUVs at pH 5 and below but inhibits it at pH 7.4. A substitution of up to 80% of the PS by the uncharged phosphatidylcholine does not impair the extent of phospholipid intermixing at pH 4. The high binding capacity of PS LUV, the disappearance of the inhibiting action, and a calculated increase of the annexin V hydrophobicity make it likely that annexin V is able to penetrate into the membrane at low pH. At neutral pH, annexin V molecules act as steric barriers, preventing close apposition of two vesicles. At pH 5, annexin V lowers the threshold concentration of the Ca2+-induced phospholipid intermixing. Such a promotion is well-known for annexin VII (synexin). The effect may be related to the isoelectric points of the two annexins which have been reported as 4.8 (annexin V) and 7.0 (annexin VII), respectively.

Annexin A5↗
PubMed1997

An essential role for CD44 variant isoforms in epidermal Langerhans cell and blood dendritic cell function.

Upon antigen contact, epidermal Langerhans cells (LC) and dendritic cells (DC) leave peripheral organs and home to lymph nodes via the afferent lymphatic vessels and then assemble in the paracortical T cell zone and present antigen to T lymphocytes. Since splice variants of CD44 promote metastasis of certain tumors to lymph nodes, we explored the expression of CD44 proteins on migrating LC and DC. We show that upon antigen contact, LC and DC upregulate pan CD44 epitopes and epitopes encoded by variant exons v4, v5, v6, and v9. Antibodies against CD44 epitopes inhibit the emigration of LC from the epidermis, prevent binding of activated LC and DC to the T cell zones of lymph nodes, and severely inhibit their capacity to induce a delayed type hypersensitivity reaction to a skin hapten in vivo. Our results demonstrate that CD44 splice variant expression is obligatory for the migration and function of LC and DC.

Animals↗
PubMed1997

Impaired macrophage listericidal and cytokine activities are responsible for the rapid death of Listeria monocytogenes-infected IFN-gamma receptor-deficient mice.

IFN-gamma receptor-deficient (IFN-gammaR -/-) mice were used to study the innate immune responses during infection with Listeria monocytogenes. Mutant mice were unable to limit bacterial growth and died of sepsis even with an infection dose of 70 Listeria. At day 2, they showed an exacerbated listeriosis and mice succumbed to infection before the onset of an effective specific immunity, demonstrating a defective innate immunity. Recruitment and extravasation of phagocytic cells to infected organs was present and dominated by neutrophils. However, during the early course of infection, mutant mice responded by an elevated inflammatory type 1 cytokine response, as determined by IL-12, IFN-gamma, TNF-alpha, and IL-1alpha-specific RNA expression. Induction of inducible nitric oxide synthase was present and also increased in mutant mice. Interestingly, IFN-gammaR -/- neutrophils expressed substantial TNF-alpha- and IL-1alpha-specific RNA, suggesting a substantial contribution in the overall inflammatory cytokine response. In contrast, IFN-gammaR -/- macrophages showed reduced MHC class II surface expression levels and impaired TNF-alpha and IL-1alpha but normal IL-6 production after restimulation with heat-killed L. monocytogenes. Moreover, IFN-gammaR -/- macrophages showed defective listericidal activities. In contrast to normal macrophages, Listeria escaped rapidly from the phagosome in IFN-gammaR -/- macrophages to the cytoplasm, where they productively survived. In conclusion, these data suggest that IFN-gammaR signaling activates yet unknown functions in macrophages, preventing Listeria-induced escape from the phagosome and consequent killing of the invader. Together with the impaired cytokine responses, these macrophage defects seem to be responsible for the dramatic susceptibility during innate immunity, whereas predominant neutrophil responses mediate limited protective role in mutant mice.

Animals↗
PubMed1997

Both innate and acquired immunity to Listeria monocytogenes infection are increased in IL-10-deficient mice.

IL-10-deficient mice were highly resistant to Listeria monocytogenes during the course of infection. An increased innate immunity was suggested by reduced bacterial burdens (as much as 50-fold) early (days 2 and 3) in the infection, as compared with control mice. In addition, in vitro stimulation of both IL-10-deficient peritoneal exudate cells and spleen cells with heat-killed Listeria resulted in a dramatically enhanced proinflammatory cytokine response (e.g., IL-12, IFN-gamma, TNF-alpha, IL-1alpha, and IL-6). During later stages of a primary Listeria infection, the reduced bacterial burden in the infected organs of IL-10-deficient mice was accompanied by decreased tissue damage and earlier clearance of the pathogen, as well as a stronger Th1 polarization. The absence of IL-10 did not influence membrane-bound factors that stimulate Th cell responses, demonstrated by the finding of normal MHC class II, B7.1, and B7.2 surface expression on F4/80+ macrophages in vivo. IL-10-deficient mice were also more resistant to a secondary infection, accompanied by an enhanced Th1 response. The results presented in this work demonstrate that the absence of IL-10 augments innate and acquired immunity during primary and secondary L. monocytogenes infection by up-regulating proinflammatory type 1 cytokine responses. The resulting protective Th1 responses lead to an effective reduction of bacterial growth and tissue destruction and to an earlier clearance of the bacteria. The physiologic role of IL-10 during L. monocytogenes infection studies is discussed and compared with pathogenic infections that induce a more systemic cytokine response in IL-10-deficient mice.

Animals↗
PubMed1997

CD22 is a negative regulator of B-cell receptor signalling.

BACKGROUND: . Antibody responses are triggered by binding of antigen to the B-cell antigen receptor (BCR). The strength of the resulting signal determines the outcome of the response, which may vary from the induction of tolerance to the antigen, to the production of specific high-affinity antibodies. Additional cell-surface proteins assist the BCR in its function, and can facilitate or inhibit an antibody response. CD22 is a BCR-associated transmembrane protein, the cytoplasmic tail of which contains three immunoreceptor tyrosine-based inhibitory motifs. These motifs are phosphorylated upon BCR-crosslinking, and can bind the tyrosine phosphatase SHP-1, a putative negative regulator of signalling from the BCR. In order to assess the role of CD22 in vivo, we have generated CD22(-/-) mice by targeted gene inactivation. RESULTS: . In CD22(-/-) mice, B-cell development is normal. There are normal numbers of peripheral B cells, but these have a more mature phenotype. In addition, recirculating B cells are absent from the bone marrow. However, the distribution of the two B-cell subtypes, B-1 and B-2, is normal. After BCR-crosslinking in vitro, splenic CD22(-/-) B cells show an increased Ca2+ influx and a lower survival due to an increased induction of apoptosis. In contrast, there is an increased proliferative response to the B-cell mitogen lipopolysaccharide (LPS). A shorter average lifespan in the B-cell compartment is also found in vivo. Furthermore, T-cell independent immune responses are impaired, whereas T-cell dependent responses are normal. CONCLUSIONS: . The absence of CD22 expression lowers the signalling threshold for BCR-crosslinking and can thus influence the fate of the B cell. We propose that the low threshold leads to hyperresponsiveness of the B cells and a chronic basal activation. In this model, engagement of the receptor without T-cell help leads to an increased induction of apoptosis, thus explaining the shorter lifespan of CD22(-/-) B cells and the low response to T-cell independent antigens. The alteration in B-cell phenotype and the higher levels of LPS-reactivity are attributable to the chronic basal stimulation.

Animals↗
PubMed1997

Altered erythrocytes and a leaky block in B-cell development in CD24/HSA-deficient mice.

The heat stable antigen (HSA, or murine CD24) is a glycosyl phosphatidylinositol-linked surface glycoprotein expressed on immature cells of most, if not all, major hematopoietic lineages, as well as in developing neural and epithelial cells. It has been widely used to stage the maturation of B and T lymphocytes because it is strongly induced and then repressed again during their maturation. Terminally differentiated lymphocytes, as well as most myeloid lineages, are negative for HSA. Erythrocytes are an exception in that they maintain high levels of HSA expression. HSA on naive B cells has been shown to mediate cell-cell adhesion, while HSA on antigen-presenting cells has been shown to mediate a costimulatory signal important for activating T lymphocytes during an immune response. Here, we characterize mice that lack a functional HSA gene, constructed by homologous recombination in embryonic stem cells. While T-cell and myeloid development appears normal, these mice show a leaky block in B-cell development with a reduction in late pre-B and immature B-cell populations in the bone marrow. Nevertheless, peripheral B-cell numbers are normal and no impairment of immune function could be detected in these mice in a variety of immunization and infection models. We also observed that erythrocytes are altered in HSA-deficient mice. They show a higher, tendency to aggregate and are more susceptible to hypotonic lysis in vitro. In vivo, the mean half-life of HSA-deficient erythrocytes was reduced. When infected with the malarial parasite Plasmodium chabaudi chabaudi, the levels of parasite-bearing erythrocytes in HSA-deficient mice were also significantly elevated, but the mice were able to clear the infection with kinetics similar to wild-type mice and were immune to a second challenge. Thus, apart from alterations in erythrocytes and a mild block in B-cell development, the regulated expression of HSA appears to be dispensable for the maturation and functioning of those cell lineages that normally express it.

Animals↗
PubMed1997

A phase-I clinical study of autologous tumor cells plus interleukin-2-gene-transfected allogeneic fibroblasts as a vaccine in patients with cancer.

Tumor cells transfected to express immunostimulatory cytokines, or admixed with similarly modified bystander cells, are able to induce immune responses against unmodified tumor cells in animal models. For treatment of human patients, a vaccine composed of autologous tumor cells and IL-2-secreting allogeneic fibroblasts was developed. Autologous tumor cells were isolated from biopsy specimens. A clone (KMST 6.14) of an immortalized human fibroblast line that stably secreted 5290 IU IL-2 per 10(6) cells and per 24 hr was obtained by cationic lipofection with an expression construct for human IL-2 and Neo(r). Fifteen patients with refractory malignant tumors received 3-4 injections of irradiated KMST6.14 and autologous tumor cells in a phase-I clinical trial. Increasing transient inflammatory responses without systemic toxicity developed at vaccination sites and after injections with irradiated tumor cells only (p < 0.05). These sites contained a dense infiltrate of CD3+ T cells with numbers of CD4+ helper cells exceeding those of CD8+ cytotoxic T cells (CTL). CD8+ T-cell lines isolated from vaccination sites of 2 malignant melanoma patients but not of renal-cell carcinoma patients exhibited a dominant lytic activity against autologous tumor cells in vitro. CD8+ T-cell clones established from the vaccination site of 1 of 2 renal-cell carcinoma patients preferentially lysed autologous and partially matched allogeneic renal-cell carcinoma cells. In conclusion, a vaccine composed of IL-2 gene-transfected allogeneic fibroblasts and autologous tumor cells is able to enhance specific anti-tumor T-cell responses in vivo without major side-effects. Malignant melanoma and renal-cell carcinoma appear to be promising entities for testing of similar approaches in future therapeutic trials.

Adult↗
PubMed1997

Induction of tumor-specific cytotoxic T lymphocytes by immunization with autologous tumor cells and interleukin-2 gene transfected fibroblasts.

In a phase I trial designed to study a vaccine composed of autologous tumor cells and interleukin-2 gene transfected fibroblasts we analyzed lymphocytes infiltrating the vaccination site (VIL) in two melanoma patients. Functional studies demonstrated that numbers of MHC class I restricted cytotoxic T cells directed against the autologous tumor had increased at the immunization site in both cases. Analysis of the variability of T cell receptors (TCR) in the VIL of one patient revealed that the cytotoxic T lymphocytes consisted of a predominant population of TCRBV21S3+ T cells. Enrichment of this subpopulation to more than 99% by specific anti-TCRBV21S3 monoclonal antibody linked immunomagnetic beads and sequencing of the TCR-beta chain disclosed exactly the same V-D-J junctional sequence in all eight TCRBV21 transcripts from these VIL. The identical sequence was also detected in all eight TCRBV21 transcripts from the patient's tumor-infiltrating lymphocytes, indicating that the same CTL clone had infiltrated the tumor, circulated in the peripheral blood, and was amplified at the vaccination site. The TCRBV21S3+ T cells were also found to display an MHC class I restricted cytotoxic activity specifically directed against the autologous tumor cells. At the beginning of treatment these cells were undetectable at the vaccination site and delayed-type hypersensitivity testing was negative, contrasting with the positive results after therapy. Thus it is likely that vaccination with autologous tumor cells plus interleukin-2 gene transfected allogeneic fibroblasts had induced not only local accumulation but also an increase in the frequency of circulating tumor specific CTL.

Amino Acid Sequence↗
PubMed1997

CD34+ peripheral blood progenitor cell and monocyte derived dendritic cells: a comparative analysis.

Dendritic cells (DC) have been generated in vitro from either CD34+ haemopoietic progenitor cells (HPC) or peripheral blood monocytes (Mo) in the presence of specific cytokine combinations, including granulocyte-macrophage colony-stimulating factor (GM-CSF). Since differences between DC from either source may be important for the clinical use of these antigen-presenting cells (APC), a comparative analysis was performed. HPC were expanded in the presence of interleukin (IL)-3, IL-6 and stem cell factor (SCF) (days 1-7) and subsequently induced by IL-4+ GM-CSF (days 8-26) to differentiate to Langerhans-type cells (pLC). The latter cytokines were similarly used to generate Mo-derived LC (mLC). Maturation of both cell types, pLC and mLC, to interdigitating DC-type cells (iDC) was induced by tumour necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS). Analysis of mLC/pLC and miDC/piDC with respect to morphology, phenotype, antigen uptake and presentation revealed a high similarity of DC from either source. The majority of mLC, however, exhibited a more mature differentiation stage, compared to pLC, evidenced from lower numbers of multilaminar MHC class II compartments and less efficient APC function for extracellular protein antigens. Although macropinocytosis was performed by LC, neither LC nor iDC from either source were able to take up > or = 0.5 microm latex beads. However, phagocytosis of 0.5 microm and 1 microm beads was performed by Mo that could subsequently be induced to become iDC, thus providing the unique opportunity to present phagocytosed material in DC-type fashion. Mo may be the preferential source for clinical use of iDC-type cells since preparation and culture are easier to perform and are less costly while APC function is similar to HPC-derived iDC.

Antigens, CD34↗
PubMed1997

Processing of tumor tissues for vaccination with autologous tumor cells.

Vaccination with gene-transfected tumor cells has recently been proposed as a new strategy in the immunotherapy of cancer. Since autologous tumor cells provide an optimal antigen profile, the possibility of generating single cell suspensions from renal cell carcinoma (RCC), malignant melanoma (MM), colon carcinoma (CC), and non-small-cell lung cancer (NSCLC) biopsies was investigated. One hundred and seventy-four tumor biopsies were processed by mechanic and enzymatic dissociation, yielding 1-2 x 10(6) cells/g tumor (median), irrespective of tumor type. Primary tumor cell cultures (PTCC) of > or = 10(7) cells were established from 29 of 86 (34%) RCC, 14 of 38 (37%) MM, 11 of 23 (48%) NSCLC and 4 of 27 (15%) CC specimens. The amount of non-tumor cells, as assessed by morphology and immunocytology, was generally low (< 30%) in RCC (35 of 41) and MM (11 of 17), while it exceeded 60% in 8 of 11 PTCC from NSCLC and 3 of 11 CC. A high tumor cell yield was obtained in biopsies with a high degree of vascularization and in the virtual absence of necrosis. Thus, PTCC > or = 10(7) cells were obtained in 73% of MM with a high degree of vascularization and in 22% of MM with a low degree of vascularization (p < 0.007). Long-term tumor cell cultures exceeding 20 passages were established in 24 of 86 (18%) RCC, 7 of 38 (18%) MM and 3 of 27 (11%) CC, while successful implantation in nude mice was achieved in 8 of 20 RCC and 5 of 10 MM. Thus, under the conditions described, > or = 10(7) primary tumor cells of high purity could be generated from about one third of RCC and MM biopsies, while the success rate increased to > 50 and > 70%, respectively, in samples with a high degree of vascularization generated by an optimized biopsy technique excluding necrotic parts.

Animals↗
PubMed1997

Paclitaxel and epirubicin as first-line therapy for patients with metastatic breast cancer.

Paclitaxel (Taxol), has aroused considerable interest for its high single-agent activity in breast cancer and novel mechanism of action. Epirubicin (Farmorubicin), the 4'epimer of doxorubicin (Adriamycin), also has high activity in breast cancer, with the advantage of a lower rate of toxic side effects-especially cardiac effects-compared with its parent compound. The combination of paclitaxel and doxorubicin has yielded response rates between 63% and 94% in phase I/II studies, but authors reported severe cardiac toxic events. The goal for the current study was to evaluate the combination of paclitaxel and epirubicin, focusing mainly on cardiac toxicity. Of a total of 85 patients entered, 68 patients with metastatic breast cancer were evaluable. Nearly 20% had primary metastatic breast cancer with large tumors. Half had received adjuvant chemotherapy. Study medication in Group A consisted of 60 mg/m2 epirubicin given over 1 hour, followed by paclitaxel 175 mg/m2 as a 3-hour IV infusion. In Group B, 90 mg/m2 epirubicin was combined with 175 mg/m2 paclitaxel, delivered as for Group A. The main toxicity in both groups was neutropenia. In Group A, the paclitaxel dose could be escalated to 200 mg/m2 in 15 patients and to 225 mg/m2 in 7 patients; dose reduction due to severe neutropenia was necessary in 11 patients. No cardiac adverse events were reported in Group A. In Group B, only one patient could be escalated to 200 mg/m2 but three patients required a dose reduction. In this group, one patient had a decrease of left ventricular ejection fraction of more than 10% without any clinical signs. Of 43 patients in Group A and 25 in Group B, the response rate was 67% in Group A and 68% in Group B. The duration of response was 8.2 months in both groups. The combination of paclitaxel 175 mg/m2 and epirubicin 60 mg/m2 or 90 mg/m2 can be safely administered. The response data were encouraging and further evaluation is warranted.

Antibiotics, Antineoplastic↗
PubMed1997

Phase II study of paclitaxel and epirubicin as first-line therapy in patients with metastatic breast cancer.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane used in routine clinical practice, has aroused considerable interest for its high single-agent activity against breast cancer and for its novel mechanism of action. Epirubicin, the 4' epimer of doxorubicin, is another agent with a high activity against breast cancer and is known for its lower rate of toxic side effects, especially toxic cardiac events, compared with its mother compound. The combination of paclitaxel and doxorubicin yielded response rates between 63% and 93% in phase I/II studies. In these studies, however, the investigators reported severe cardiac toxic events. The rationale for the current study was therefore to evaluate the combination of paclitaxel/epirubicin, focusing mainly on cardiac toxicity. In two groups, 85 patients with metastatic breast cancer entered the study. Approximately 20% of the patients had primary metastatic breast cancer with large tumors at the primary site. Half of the patients had received adjuvant chemotherapy. Study medication in group A consisted of epirubicin 60 mg/m2 given intravenously over 1 hour, followed by paclitaxel 175 mg/m2 administered as a 3-hour intravenous infusion after premedication with steroids, antihistamines, and H2-blockers. In group B, epirubicin 90 mg/m2 was combined with paclitaxel 175 mg/m2, given in the same manner as in group A. Dose escalation to 225 mg/m2 paclitaxel was planned in both groups. The main toxicity in both groups was neutropenia (73% World Health Organization grade 3/4 in group A and 93% in group B). Other hematologic side effects were rare. No febrile neutropenia was reported in group A, but two episodes occurred in group B. Peripheral neuropathy, arthralgia, and myalgia were mild (only World Health Organization grades 1 and 2). Alopecia was universal. In group A, the paclitaxel dose could be escalated to 200 mg/m2 in 15 patients and to 225 mg/m2 in seven patients. Dose reduction due to severe neutropenia was necessary in 11 patients. No cardiac events were reported in group A. In group B, the paclitaxel dose could be escalated to 200 mg/m2 in only one patient, and no patient reached 225 mg/m2. Three patients needed a dose reduction. In this group, one patient had a greater than 10% decrease in the left ventricular ejection fraction with no clinical signs. In group A, 43 patients were evaluable for response; in group B, 25 patients were evaluable. Thirteen patients were out of protocol with only bone metastasis, and two patients had more than one prior chemotherapy for metastatic disease. The response rate was identical in both groups, with five complete remissions and 24 partial remissions in group A and three complete responses and 14 partial remissions in group B. The duration of response was 8.2 months in both groups. The median cumulative epirubicin dose was 420 mg/m2 in group A and 630 mg/m2 in group B. The combination of paclitaxel 175 mg/m2 and epirubicin 60 or 90 mg/m2 can be administered safely to patients with metastatic breast cancer. Although response was not the primary end point of this trial, the response data are nonetheless encouraging and suggest that further evaluation of this combination-line treatment of metastatic breast cancer is warranted.

Adult↗
PubMed1997

[Initial experiences and outcome of gasless laparoscopic pelvic lymph node excision combined with Schauta vaginal radical hysterectomy in stage IB cervix carcinoma].

In 11 patients with a cervical cancer stage IB a gasless laparoscopic pelvic lymph node dissection in combination with a vaginal radical Schauta-Amreich-hysterectomy was performed. The technique of the gasless lymph node dissection with the Laparolift (ORIGIN Medsystems, Menlo Park) is described. Because of the advantages of this technique (ability to use conventional and endoscopic instruments, perform irrigation and suction, dot with sponge sticks, change instruments quickly, prepare and remove lymph nodes without influence on visibility) it was possible to obtain a radicality (45 lymph nodes-median value) according to oncological standards for an abdominal radical Wertheim hysterectomy. If the radicality is equivalent to a Wertheim hysterectomy the combination of the radical vaginal Schauta-Amreich-hysterectomy and the gasless laparoscopic pelvic lymph node dissection offers a real alternative to the abdominal Wertheim hysterectomy because of low postoperative morbidity and quick mobilisation.

Adenocarcinoma↗