Assessing the TP53 marker type in patients treated with or without neoadjuvant chemotherapy for resectable colorectal liver metastases: a p53 Research Group study.

The type of a biomarker - whether it is prognostic or predictive - is frequently not known, although such information is crucial for assessing the clinical value of a marker. In order to evaluate the type of marker TP53 is, we identified a cohort of 76 patients with colorectal liver metastases (CLM), homogeneously staged as resectable, who had been treated either with or without fluorouracil-based neoadjuvant chemotherapy. The TP53 genotype was assessed retrospectively from paraffin-embedded, diagnostic tumour biopsies using a standardised, p53 gene-specific sequencing protocol (mark53(®) kit). The overall median survival was 44.2 months, and the overall TP53 mutation frequency was 55%. A significant interaction was observed between chemotherapy and TP53 status (P = 0.045). To illustrate this effect, the 51 patients with and the 25 patients without neoadjuvant chemotherapy were described separately. In patients with neoadjuvant chemotherapy, mutated TP53 was significantly associated with poor survival (P = 0.0025), resulting in five-year survival rates of 22%, compared to 60% in patients with normal TP53. The hazard ratio was 3.12 (95% confidence intervals (CI): 1.46-6.95) to the disadvantage of TP53-mutated patients and 5.49 (P = 0.0001; 95% CI: 2.28-13.24) after adjustment for known prognostic factors. In patients treated with surgery alone, a mutated TP53 did not have a negative effect on survival (P = 0.54). A mutated TP53 status independently predicted survival disadvantage in CLM patients in the presence, but not in the absence, of neoadjuvant chemotherapy. Our data suggest that TP53 might be a pure predictive marker.

Kinetics of PBPC mobilization by cyclophosphamide, as compared with that by epirubicin/paclitaxel followed by G-CSF support: implications for optimal timing of PBPC harvest.

BACKGROUND: Limited information is available on the mobilization kinetics of autologous PBPCs after induction with various chemotherapy regimens. With PBPC mobilization in patients with breast cancer used as a model for chemotherapy-induced PBPC recruitment, the kinetics of progenitor cells mobilized either with cyclophosphamide (CY) or epirubicin/paclitaxel (EPI-TAX) followed by the administration of G-CSF was compared. STUDY DESIGN AND METHODS: The study included a total of 86 patients with breast cancer (stage II-IV) receiving either CY (n = 39) or EPI-TAX (n = 47), both followed by G-CSF support. The progenitor cell content in peripheral blood and apheresis components was monitored by flow cytometric enumeration of CD34+ cells. PBPC collection was started when the threshold of >20 x 10(6) CD34+ cells per L of peripheral blood was reached. RESULTS: The PBPC collection was begun a median of 9 days after the administration of EPI-TAX followed by G-CSF support, as compared to a median of 13 days after mobilization with CY plus G-CSF. After treatment with CY, the total numbers of PBPCs peaked on Day 1 of apheresis, and they rapidly declined thereafter. In contrast, treatment with EPI-TAX followed by G-CSF administration led to a steady mobilization of CD34+ cells during leukapheresis. The difference in the mobilization patterns with CY and EPI-TAX resulted in a greater yield of CD34+ cells per L of processed blood volume. Compared to EPI-TAX, mobilization with CY required the overall processing of 30 percent less whole-blood volume to reach the target yield of > or = 10 x 10(6) CD34+ cells per kg of body weight. After a median of three apheresis procedures, however, both CY+G-CSF and EPI-TAX+G-CSF were equally effective in obtaining this target yield. CONCLUSION: These results imply that specific PBPC mobilization as part of a given chemotherapy regimen should be taken into consideration before the planning of a PBPC harvest.

The use of dose-intensified chemotherapy in the treatment of metastatic nonseminomatous testicular germ cell tumors. German Testicular Cancer Study Group.

With the use of a cisplatin-based chemotherapy, metastatic testicular cancer has become a model for a highly curable malignant disease. Current data show that 70% to 80% of patients with this disease will achieve long-term survival following cisplatin/etoposide/bleomycin therapy. The role of high-dose chemotherapy with autologous stem cell support is being investigated in metastatic germ cell cancer in attempts to improve outcome for patients whose disease relapses after standard-dose chemotherapy and for those who present initially with advanced metastatic disease. Prognostic categories for patients receiving high-dose salvage chemotherapy have recently been developed: cisplatin-refractory disease, beta-human chorionic gonadotropin values greater than 1,000 U/L, and primary mediastinal germ cell tumors are factors characterizing patients who will derive less benefit from high-dose chemotherapy than those with chemosensitive disease at relapse. While standard-dose salvage chemotherapy achieves only a 20% long-term survival rate, high-dose salvage chemotherapy may yield a cure rate of approximately 40%. A randomized study comparing high-dose therapy with conventional-dose therapy (IT94 coordinated by the European Group for Blood and Marrow Transplantation) in patients with relapsed disease is ongoing to substantiate this observation. The use of dose-intensive therapy as first-line treatment is currently being studied by several institutions. High-dose therapy may be better tolerated when used first line compared with its use in the salvage situation, and may also achieve a rapid initial cell kill before cytostatic drug resistance develops. The German Testicular Cancer Study Group has developed a sequential high-dose combination regimen of cisplatin/etoposide/ifosfamide given with granulocyte colony-stimulating factor and peripheral blood stem cell support for four cycles every 3 weeks. This ongoing study, started in 1990, had accrued 218 patients with advanced testicular germ cell tumors as of June 1997. Of 141 evaluable patients receiving dose levels 1 through 5, 82 (58%) have achieved complete remission with no evidence of disease and 32 (23%) have achieved partial remission with marker normalization. The early death rate was 8%. Overall and event-free survival rates at 2 years are 78% and 73%, respectively, with a projected 5-year overall survival rate of 74%. Despite favorable preliminary results, this approach cannot be considered standard treatment. Currently, high-dose chemotherapy with peripheral blood stem cell transplantation should be administered to patients with testicular cancer only within controlled clinical trials to allow long-term cure rates and treatment-related late side effects to be evaluated.

Secondary migration: a complication of Hickman central venous catheters.

We report two patients with spontaneous intrajugular migration of Hickman catheters which were initially correctly placed with the tip in the right atrium, via the right subclavian vein. In one patient the catheter remained in situ for 40 days without any sequelae; in the second patient the catheter was removed immediately. In the first patient two interim chest radiographs disclosed the catheter's course suggesting a possible mechanism of migration. Since early detection of this complication allows interventional repositioning, periodic monitoring of indwelling catheters by chest X-ray is recommended.

[The treatment of multiple myeloma]. / Die Behandlung des multiplen Myeloms.

Median survival in patients with multiple myeloma, which amounted to 6-12 months during the pre-chemotherapy era, was improved to 28-43 months following the introduction of chemotherapy. Usually patients with stage II or III myeloma require treatment. Conventional chemotherapy with melphalan-prednisone is undertaken if their prognosis is good; in case of poor prognosis and good general condition, a more aggressive polychemotherapy is given. High-dose melphalan therapy alone induces high remission rates, but fails to prolong remission duration or survival. Resistance to cytostatic drugs due to the p-glycoprotein coded by the MDR-gene is treated by a combination of cyclosporin-A or verapamil and VAD. For the treatment of relapses or of primarily resistant patients several second-line regimens are available. As remission maintenance therapy, interferon has so far yielded the best results. Trials of other cytokines such as interleukin-2 and interleukin-4 are still inconclusive. For autologous bone marrow transplantation, primary reduction of the tumour mass by conventional polychemotherapy is recommended. Subsequently, high-dose melphalan or cyclophosphamide-busulfan--with or without total body irradiation--is used for conditioning and followed by the transplantation of either autologous bone marrow or peripheral blood stem cells. Significantly higher remission rates and longer survival of the patients may be expected. Allogenous bone marrow transplantation is burdened with a high early mortality rate, but it also promises longer disease-free survival times. Bone marrow transplantation should be performed as early as possible in the course of the disease. More controlled studies are required before a definite evaluation of its efficacy is possible.

[Germ cell tumors of the testis]. / Keimzelltumoren des Hodens.

Testicular cancer is the most common malignancy in men aged 15 to 30 years. In the 1990s testicular cancer has become one of the most curable solid neoplasms, and it can serve as a paradigm for the multimodal treatment of solid malignancies, making even a metastasized cancer a curable disease. The dramatic improvements in survival have occurred as a result of the combination of effective diagnostic techniques, improvement in serum tumour markers, modification of surgical technique and, above all, the development of highly effective multidrug chemotherapeutic regimens based on cisplatin. In the 1990s overall survival for all stages of testicular cancer should be well above 80% and should approach 100% for patients with low stage disease. Important studies forming the basis for the most up to date multimodality treatment are reviewed in this article. Alternative strategies for salvage therapy in poor risk patients and those who failed to respond to treatment are discussed, as well as minimization of toxicity in low risk patients.

Erythropoietin treatment for chronic anemia of selected hematological malignancies and solid tumors.

BACKGROUND: Neoplasias, especially in their more advanced stages, are often associated with chronic anemia of malignancy which impairs the patient's physical ability and quality of life. PATIENTS AND METHODS: Forty-two patients with chronic anemia associated with hematological malignancies (18 multiple myelomas, 10 myelodysplastic syndromes) or solid tumors (9 breast cancers, 5 colon cancers) were treated with 150-300 units/kg rHuEPO for a median time period of 16 weeks. Response was defined as an increase of the initial hemoglobin level by at least 2 g/dl. RESULTS: The response rates for solid tumors were comparable (44.4% and 40% for breast cancer and colon cancer, respectively), whilst the response in patients with hematological malignancies depended strongly on the disease entity (77.8% for multiple myeloma, 10% for myelodysplastic syndrome). Pretreatment serum levels of endogenous erythropoietin (EPO) were significantly higher in non-responding patients than in responders. During rHuEPO therapy, EPO levels in non-responders increased even further, while they remained basically unchanged in responding patients. In responders, the WHO performance status before the start of rHuEPO therapy was more favorable and showed impressive improvement during the course of treatment. The median survival time of responders was 28.0 months as compared to only 9.2 months for non-responders. Clinical symptoms of anemia subsided or at least considerably improved under successful rHuEPO therapy. With the exception of occasional flu-like symptoms, no undesirable effects of rHuEPO treatment were observed. CONCLUSIONS: In conclusion, rHuEPO treatment corrected anemia of malignancy both in patients with hematologic disease and in those with solid tumors, but responsiveness varied considerably amongst the different disease entities.

Risk factors for bilateral testicular germ cell tumors. Does heredity play a role?

Twenty-three bilateral testicular germ cell tumors (four synchronous and 19 sequential tumors) were investigated for potential risk factors. The incidence of maldescensus testis was not found to be higher than in patients with unilateral disease. The histologic findings of the first tumor did not have any effect on the incidence of the second tumor. In 21 patients (four synchronous and 17 sequential tumors), histocompatibility antigens (HLA) were determined; HLA-B14 was increased significantly in the sequential tumor group. Tendencies toward an increase of HLA-DR5 and HLA-DR7 also were found. The HLA-DR1, HLA-DR3, and HLA-DR4 showed a tendency toward a decreased frequency. Therefore genetic factors might be important in the development of sequential bilateral testicular cancers.

[Effect of various factors on survival after recurrent and/or metastatic breast cancer]. / Der Einfluss verschiedener Faktoren auf das Uberleben des rezidivierenden und/oder metastasierenden Mammakarzinoms.

145 women (22.2%) out of 652 patients with primary breast cancer, who were operated on between January 1980 and September 1988, developed tumour relapse until May 1990. The aim of our retrospective analysis in these 145 patients with local and/or distant tumour relapse was to evaluate the prognostic importance for further survival of the following factors: menopausal status, stage of disease, number of involved axillary lymph nodes, tumour grading, ER and PgR content, postoperative irradiation, adjuvant treatment, localisation of tumor relapse and relapse-free interval. Multivariate stepwise regression analysis of all these factors identified the number of positive axillary lymph nodes (0-3 versus 4+) with a relative risk (RR) of 2.49 and localisation of tumour relapse (local versus visceral metastasis RR = 2.08 and local versus bone metastases RR = 2.08) as the only two significant prognostic factors for further survival. Therefore, these two factors should be stratification criterias for prospectively randomized phase III studies in patients with tumour relapse after primary breast cancer.

Combined alpha-2C-interferon/VMCP polychemotherapy versus VMCP polychemotherapy as induction therapy in multiple myeloma: a prospective randomized trial.

Thirty-three previously untreated patients with multiple myeloma were randomized to either a combination of recombinant interferon-alpha-2C (rIFN-alpha-2C) plus vincristine/melphalan/cyclophosphamide and prednisone (VMCP) or VMCP chemotherapy alone. The combined regimen effected 67% responses and 26% minor responses, while 35 and 47% of VMCP-treated patients had a pathologically documented remission, respectively. Despite the somewhat earlier achievement and duration (12.0 vs. 8.0 months) of objective response, and the marginal survival benefit observed in the rIFN-alpha-2C + VMCP treatment arm, a significant improvement in therapeutic gain by adding a biologic response modifier to conventional first-line polychemotherapeutic drug treatment in myeloma patients has not yet been achieved. The combined regimen was well tolerated without unusual or unexpected toxic effects.

[Interferon therapy in multiple myeloma]. / Die Interferontherapie beim multiplen Myelom.

Natural leukocyte interferon and recombinant interferon alpha-2 have effected remission rates between 10 and 20% in the treatment of multiple myeloma. Response rates have been higher in untreated patients than in relapsing or primarily refractory cases. Patients with slowly proliferating tumors, early tumor stage or IgA-monoclonal protein seem to show increased sensibility to interferon as compared to patients without those characteristics. First trials using combined interferon chemotherapy regimens suggest that the toxicity associated with this treatment modality remains acceptable. At present, however, one cannot definitely decide whether and to which degree the combination therapy will improve the response rates.

[Results of chronic hemodialysis treatment in patients with diabetic nephropathy]. / Ergebnisse der chronischen Hämodialysebehandlung bei Patienten mit diabetischer Nephropathie.

In order to evaluate the differences in morbidity and mortality of diabetics on haemodialysis (HD), data on 12 patients with diabetic nephropathy and 14 non-diabetic patients have been analyzed retrospectively since 1982. The groups were matched for sex, age and duration of HD. We analyzed the differences in survival rate, the number of hospitalization days and the causes of death. Values of BUN, creatinine, calcium, phosphate, cholesterol and triglycerides, alkaline phosphatase, erythrocyte count and haemoglobin were compared throughout the dialysis period. No significant differences occurred between the two groups as regards blood chemistry values (except for creatinine) throughout the observation period. The number of hospitalization days per month of dialysis was significantly different: 1.8 days in diabetic versus 0.9 days in non-diabetic patients (p less than 0.005). This difference is due to a higher rate of vascular access complications and infections. The 3-year survival rate on HD was 73% in type I diabetics (controls 93%), while none of the type II diabetics survived for more than 24 months on HD. The most common causes of death in the diabetic patients were cardiovascular (44%) and septic (44%) complications, followed by cerebrovascular problems (12%). We conclude from our study that the reason for the poor prognosis of diabetic patients on HD is not lack of efficiency of the procedure, but progression of the multisystemic diabetic condition.