Idiopathic autoimmune thrombocytopenia: evidence for redistribution of platelet antibodies into the circulation after immunoadsorption treatment.

Platelet antibodies are detectable in only about 50% of patients with chronic autoimmune thrombocytopenia (AITP). We determined platelet antibodies against GPIa/IIa, GPIb/IX, GPIIb/IIIa, and GPV and reticulated platelets in three female patients with AITP, before and after immunoadsorption treatment. None of the three patients' sera contained platelet antibodies prior to treatment. Thereafter, anti-GPIIb/IIIa, anti-GPIb/IX (n = 3), and anti-GPV (n = 1) were detectable in the patients' sera. These antibody specificities were also found in the eluates from the immunoadsorption columns. Only one patient had elevated levels of reticulated platelets. Immunoadsorption treatment did not induce a sustained increase of platelet counts in any patient. Immunoadsorption treatment in AITP can induce redistribution of antibodies into the circulation.

A paraneoplastic syndrome mimicking extrauterine pregnancy.

We report on a 30-year-old female patient with a beta-human chorionic gonadotropin (beta-HCG)-producing lung tumour. Abdominal discomfort and vaginal bleeding were the presenting symptoms and, in conjunction with elevated beta-HCG levels, initially led to the diagnosis of extrauterine pregnancy. Bilateral ovarian cysts were detected on further diagnostic workup. Ultimately, a chest X-ray revealed a lung tumour. The paraneoplastic symptoms were completely reversible after resection of the lung lesion, and the ovarian cysts disappeared.

Effect of interferon alpha-2a on hormone receptor status in patients with advanced breast cancer.

The aim of this study was to assess the effect of recombinant interferon alpha-2a (rh-IFN) on estrogen (ER) and progesterone (PR) receptor expression in patients with advanced breast cancer and the evaluation of the effect of rh-IFN pretreatment on response to endocrine therapy with tamoxifen (TAM). Between June 1990 and November 1992, 20 patients with disseminated breast cancer and with metastatic skin nodules suitable for biopsy were entered into this study. Eighteen assessable patients underwent biopsy before and 2 weeks after treatment with rh-INF. rh-INF 3 x 10(6) IU were administered subcutaneously per day. Patients with ER expression at second biopsy were subsequently treated with 20 mg TAM daily. One patient had rapid disease progression and died before rebiopsy could be performed, and an additional patient refused second biopsy. All other patients were considered assessable. Thirteen patients showed ER expression before rh-IFN treatment, and 5 PR presented with expression. Rh-IFN increased ER expression in three patients and PR in four patients. No change was observed in 8 patients for ER and in 12 patients for PR. ER expression decreased in seven patients and PR expression decreased in two patients, respectively. Two patients showed a partial remission after subsequent treatment with TAM. Adverse reactions caused by rh-IFN were mainly flu-like symptoms. In this trial we found no systematic impact of rh-IFN on hormone receptor expression and, subsequently, on the response rate in patients with advanced breast cancer.

Bone resorption in multiple myeloma and in monoclonal gammopathy of undetermined significance: quantification by urinary pyridinium cross-links of collagen.

To quantify osseous breakdown in multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), and benign osteoporosis, we measured urinary levels of pyridinium cross-links of collagen in 50 patients with newly diagnosed and untreated MM, 40 patients with MGUS, 40 untreated patients with osteoporotic vertebral fractures, and 64 healthy adults. Ion-paired, reverse-phase high-performance liquid chromatography (HPLC) was used to measure total urinary excretion of pyridinoline (h-PYD) and deoxypyridinoline (h-DPD). Urinary excretion of free immunoreactive deoxypyridinoline (i-DPD) was determined with an enzyme immunoassay. MM patients had significantly (P < .0001) higher levels of h-PYD, h-DPD, and i-DPD than the healthy adults, patients with MGUS, or patients with osteoporosis. The MGUS and osteoporosis groups presented with elevated (P < .05) levels of urinary pyridinium cross-links when compared with healthy controls. In 20 MM patients who subsequently received chemotherapy, the percent changes in i-DPD did not correlate with the changes in the monoclonal protein. In one of three patients experiencing a transition of initial MGUS into stage I MM, i-DPD increased above the upper limit of the normal range. In 13 patients with stable MGUS, i-DPD remained normal in repeated measurements. Based on the upper limits of the normal range, the sensitivity of urinary pyridinium cross-links in stage I and II MM was low (<50%), but it was between 78% (h-DPD) and 93% (i-DPD) in stage III MM. Specificity in patients with MGUS was between 87% (h-PYD) and 97% (h-DPD). In conclusion, determining the urinary excretion of pyridinium cross-links seems to be a promising noninvasive and thus easily repeatable method for evaluating the actual degree of osseous breakdown. Although measurement of pyridinium cross-link levels is not useful in discriminating patients with MGUS from early-stage myeloma patients, determination of i-DPD levels may contribute importantly to clinical guidance, since increased i-DPD levels seem to identify patients who are particularly likely to benefit from osteoclast-inhibiting drugs such as bisphosphonates. The fact that in a number of patients paraprotein concentrations and i-DPD levels did not change in parallel but instead diverged strongly after chemotherapy might explain the observation that bone lesions sometimes progress even in patients who achieve complete remission.

Neoadjuvant chemotherapy (MVAC) in locally invasive bladder cancer.

In order to evaluate the efficacy of neoadjuvant chemotherapy in invasive urothelial carcinoma of the bladder a retrospective analysis was performed. 54 patients without distant metastases (T2-T3b, N0-X, M0) received 3 cycles of neoadjuvant chemotherapy according to the MVAC protocol (methotrexate, vinblastine, doxorubicin and cisplatin) after transurethral resection (TUR) followed by cystectomy. 52 patients had previously undergone cystectomy immediately after TUR. Complete histopathological remission was observed in 9 patients (17.3%) after TUR and in 17 patients (31.5%) after TUR+MVAC. Neoadjuvant MVAC resulted, therefore, in a 14% higher rate of complete remissions. The overall response to TUR was significantly improved by MVAC therapy. Downstaging by neoadjuvant chemotherapy was more readily achieved in initially low-stage tumours (T2: 44.4% and 30.8%, T3a: 47.1% and 19%, T3b: 5.3% and 5.5% in patients receiving TUR+MVAC and TUR alone, respectively). Overall survival did not differ significantly between both groups. Patients who were successfully downstaged to pT0 had a significantly better prognosis, and patients resistant to chemotherapy had the poorest prognosis, showing the shortest survival. In conclusion, histopathological response at cystectomy was improved by neoadjuvant MVAC chemotherapy after TUR and can be expected to be prognostically relevant in those patients who can be downstaged to T0, although overall survival failed to be significantly increased in this relatively small patient sample.

Maximal androgen blockade in combination with methotrexate for treatment of metastatic prostate cancer.

Recently attention has been focused on the optimal timing of chemotherapy within the treatment regimen for patients with metastatic prostate cancer, i.e., hormonal manipulation, preferably maximal androgen blockage (MAB) consisting of chemical/surgical castration followed by treatment with antiandrogens. We have conducted a randomized prospective clinical trial, investigating the efficacy and toxicity of MAB (orchiectomy followed by flutamide therapy) alone as compared to MAB combined with methotrexate (MTX, 50 mg/m2/week) in 53 patients with newly diagnosed stage IV(M1) prostatic cancer (UICC TNM Classification 1987). The observed remission rates (complete + partial) of 42.3% in the MAB + MTX arm and 29.6% in the MAB arm did not differ significantly. The response rates (complete + partial + stable disease) of 73.1% and 66.7% for MAB + MTX and MAB respectively, also showed no significant difference. Neither progression-free survival (median 18/5 and 23.8 months for MAB + MTX and MAB, respectively) nor overall survival (median: 37.4 and 36.1) months in the MAB + MTX and MAB arm, respectively) could be improved by the addition of MTX to MAB Only the extent of metastatic pain reported by the patients was consistently less under MAB + MTX than under MAB alone (P<0.1). Both treatment regimens were well- tolerated with slightly more undesirable effects in the MAB + MTX arm. Our results do not provide evidence for the achievement of marked gains by combining chemotherapy with endocrine therapy in newly diagnosed patients with stage IV (M1) prostate cancer.

Randomised study using IFN-alpha versus IFN-alpha plus coumarin and cimetidine for treatment of advanced renal cell cancer.

BACKGROUND: Treatment results in patients with metastatic renal cell cancer (RCC) are still extremely unsatisfactory. Rates of response to IFN-alpha monotherapy and/or IL-2 mono/combination therapy vary between 10% and 20%. Coumarin (Cum) together with cimetidine (Cim) has yielded objective responses in 20%-33% of patients with RCC, according to two recent phase II studies. PATIENTS AND METHODS: In the present study 148 patients with metastatic RCC were randomised to receive either IFN-alpha (5 MU 5 x weekly s.c.) + coumarin (100 mg/d p.o.) + cimetidine (3 x 400 mg/d p.o.), or IFN-alpha-monotherapy (5 MU 5 x weekly s.c.). RESULTS: Of the 148 patients in the study 137 were evaluable for response. No differences in remission rates (RR IFN-alpha + Cum + Cim 17.1% and IFN-alpha 20.8%) or survival times (median survival 9 months and 8 months, respectively) were found between these two treatment arms. CONCLUSIONS: This study confirms that INFN-alpha has antitumoral activity in RCC. Adding coumarin + cimetidine to IFN-alpha in the dose and regimen prescribed in this study did not increase response rates or survival.

Treatment of advanced colorectal cancer with folinic acid and 5-fluorouracil in combination with cisplatinum.

51 patients with metastatic colorectal cancer (stage Dukes D) were treated with intravenous (i.v.) infusion on days 1, 3, 5, 8 and 16 with folinic acid (200 mg/m2) and 5-fluorouracil (600 mg/m2), and on days 1, 8 and 16 with cisplatinum (25 mg/m2 i.v.); cycles were repeated every 4 weeks. All 51 patients were evaluable for toxicity and response criteria. 26 patients had objective responses (3 complete responses, 5.9%; 23 partial responses, 45.1%), relative risk 51% (95% confidence intervals 36.7-65.0%). Response duration ranged from 4 to 28.0 months (median 16.8). Overall median survival of all patients included was 14.7 months (range 3.0-33.0). Toxicity of WHO grade III, requiring dose reduction, occurred in 9 (18%) patients. The regimen described here appears to be active, safe and well tolerated for treatment of patients with advanced colorectal cancer.

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.

[Therapy of advanced prostatic cancer]. / Die Therapie des fortgeschrittenen Prostata-karzinoms.

Prostate cancer is a polyclonal tumor. There are about 70 bis 75% responders after hormone therapy among previously untreated patients in EORTC trials. Therefore 25 to 30% of the tumors are resistant to androgen. Surgical and hormonal castration show similar results. After progression under hormone therapy response can be reached with antiandrogenic therapy in 30 to 38%. All this leads to the conclusion that it is necessary to base treatment on tumor adaptation and selection. Cell clones insensitive to androgen therefore need cytostatic chemotherapy. It is not yet proofed whether polychemotherapy really shows better results than monotherapy does. Following the thesis of a polyclonal tumor, therapy of advanced prostate cancer must be based on hormone therapy and cytostatic chemotherapy. Prostate specific antigen is a marker for an early recognition of progression.

[High dosage ketoconazole therapy in the treatment of advanced prostatic cancer]. / Hochdosierte Ketokonazoltherapie in der Behandlung des fortgeschrittenen Prostatakarzinoms.

This paper reports on oral high-dose ketoconazole treatment (3 x 400 mg/die) in 38 patients with advanced (pT3-4NXMOGIII - n = 9), metastasizing (Ml - n = 23) prostatic cancers that had been treated previously (n = 23) or untreated (n = 15). The primary response rate was 66% with 37% remissions. After 1 year, the response rate was 40% with 8% remissions and 8% progressive tumours. There was drop-out rate of 34% because of adverse experience and a very high rate of side-effects for 74%. During treatment there was a significant reduction in testosterone, cortisol and acid phosphatase blood levels. There was a transient rise in liver enzymes (gamma-GT, GOT, GPT, LDH and bilirubin) above the limit. There was no change registered in the renal parameters (BUN, creatinine) or in the calcium and phosphorus blood levels. There was no difference in the response rate between patients who had been treated previously and those with no treatment. There was also no difference in the outcome of tumours that had metastasized and those that had not.

[Dose-related effect of dexamethasone on the poly-(ADP ribose) synthesis of human lymphocytes]. / Dosisabhängiger Einfluss von Dexamethason auf die Poly-(ADP-Ribose-)Synthese menschlicher Lymphozyten.

Poly (ADP-ribose) synthesis and DNA synthesis after medication of dexamethasone was determined in 16 cases. Poly (ADP-ribose) synthesis in peripheral lymphocytes decreased after low dose dexamethasone. In a second trial with double doses of dexamethasone no significant decrease of Poly (ADP-ribose) in relation to DNA synthesis could be shown. There seems to be a connection between suppression of Poly (ADP-ribose) and cell cyclus of lymphocytes, specially the S-phasis of lymphocytes. The decrease of Poly (ADP-ribose) synthesis after cortisone medication is dosis connected. Dosis, interval of dosis and over all dosis are closely related to the effect of immunosuppression of this steroidal hormone.

The value of the DNCB test in bladder cancer. Pretreatment evaluation of immune function and 5-year follow-up of patients with urinary bladder cancer.

In 68 patients with histologically verified tumors of the urinary bladder, cell-mediated and humoral immune parameters were investigated before therapy and the results were re-evaluated after a 5-year observation period in order to correlate them with relapse rate and survival time. Skin test reactivity, as measured with recall antigens (tuberculin, streptokinase-streptodornase, mumps, toxoplasmin and candidin), and serum levels of immunoglobulins do not differentiate between levels of invasion and grade of malignancy. However, it was found that patients with tumors of high grades of invasiveness and malignancy were anergic to the primary skin test antigen dinitrochlorobenzene (DNCB). Furthermore, a correlation between anergic reactivity to the DNCB test and absence of local inflammatory reactions at the tumor site was detected, showing that patients with a negative DNCB challenge test were those in whom no immunocytes could be detected in the intra- and peritumoral area. Survival time and incidence of relapse were also correlated with initial skin test reactivity to DNCB, i.e. all patients with tumor stage pT3 and skin test anergy developed recurrences and died within the 5-year observation period. The correlation between morphological inflammatory criteria and immunological parameters detected in patients with advanced tumor stages should therefore be taken into consideration when taking therapeutic decisions at the time of diagnosis.

[Chemo-immunotherapy in disseminated malignant testicular tumors]. / Chemoimmunotherapie disseminierter maligner Hodentumoren.

Since 1978 we have treated 26 patients with testicular cancer in stage IV with the following chemotherapy regimen: Vinblastine 6 mg/m2 (day 1 and 2) and bleomycin 30 mg given over 24 hour period (day 1 to day 5). After two cycles this therapy was changed and patients received the combination adriamycin 60 mg/m2 (day 1) and cis-DDP 20 mg/m2 (day 1 to 5) for further two cycles. We achieved 69% (18 of 26 patients) complete remissions. Patients without response or no change received as second treatment modality vincristine 0,8 mg/m2 (day 1) and ifosfamide 1500 mg/m2 (day 1 to 5). Before each chemotherapy in an interval of two days 1 Unit (= 1 KE) of OK-432 (Streptococcus pyogenes) preparation, an immunomodulating agent, was given intravenously. In the therapyfree interval of chemotherapy 2 KE of OK-432 were applied. The maintenance therapy for 1 year consisted of vinblastine and trofosfamide and also OK 432. For the achievement of complete remissions 4 courses of chemotherapy seemed to be sufficient. The inclusion of OK 432 immunotherapy in an already established chemotherapy regimen seems to be qualified due to the reduction of chemotherapy induced side effects (myelosuppression, immunodeficiency) and the immunorestoration achieved before chemotherapy.

[(General rehabilitation in oncology)]. / Generalrehabilitation in der Onkologie.

Rehabilitation has become a modern expression. For many years optimal rehabilitation has been carried out in many different sectors of illness. Too few activities, however, have been developed for the rehabilitation and control of cancer patients. No other group requires rehabilitation as foremost as that of cancer patients who need a complete and complex program which besides pure medical treatment affords psychosomatic care primarily. By developing a program under the title "Wiener Modell" (Vienna Model), our department was able to put into practice a suitable program for the control of cancer patients. The success was possible due to the excellent teamwork of doctors, nurses and therapeuts as well as the inter-disciplinary cooperation of all specialists available in a municipal modern hospital.

Serum lysozyme levels in patients with solid tumors.

Serum lysozyme has been demonstrated to be an indicator for macrophage activity in the tumor-bearing host. Therefore, we investigated lysozyme levels in the sera of 336 untreated tumor patients (121 malignant melanoma, 61 lung cancers, 70 cervical cancers, 49 breast cancers and 35 benign breast tumors, and 36 healthy controls). Patients with malignant melanoma and lung cancer had significantly higher lysozyme levels than the healthy controls. Within the clinical stages in melanoma, there was a decrease of lysozyme in stages II and III in comparison to stage I, but still above that of the control values. Patients with benign breast tumors had normal levels, whereas in breast cancer patients of stages I and II there was a significant reduction in the lysozyme levels. In stages III and IV no differences to the control group could be detected. In patients with cervical cancer (FIGO II and III) serum lysozyme levels were found to be within the normal range. From this study it can not be concluded that serum lysozyme reflects the immunological reactivity of the tumor bearer. Nevertheless, the reduced levels in stages I and II of breast cancer might point to an immunological defect.

[Clinical and immunological studies with OK-432 (Streptococcus pyogenes) on immunotherapy in cancer patients]. / Klinische und immunologische Untersuchungen mit OK-432 (Streptococcus pyogenes) zur Immuntherapie bei Krebspatienten.

In a phase I study, the bacterial vaccine OK-432 (streptococcus pyogenes) was investigated in eight patients with advanced malignant tumors. Besides a fever reaction after i.v. application no toxic side effects were observed. Additionally, its therapeutic effectiveness could be demonstrated by i.v. and local therapy. There was also observed an increase of lymphocyte blastogenesis response in patients under treatment with OK-432.

[Clinical and immunologic investigations of patients with urinary bladder tumors (author's transl)]. / Klinische und immunologische Untersuchungen bei Patienten mit Harnblasentumoren.

Forty patients with urinary bladder tumors (26 cancer and 14 papilloma) were investigated by clinical and immunological methods. Patients with Stage I and II bladder cancer had a decrease in their delayed cutaneous hypersensitivity reactions in comparison to healthy controls. The same was found in patients with proliferating papillomas (WHO I) and benign papillomas. Patients with carcinoma in Stages III and IV had a reduced reactivity to recall antigens and could be immunized to a significantly lesser degree with primary antigens. In most cases a transurethral resection of the tumor was followed by radiotherapy. In four patients local immunotherapy was performed after resection of most of the tumor mass.