Changes over time in the course of advanced pancreatic cancer treatment with systemic chemotherapy: a pooled analysis of five clinical trials from two decades of the German AIO study group.

BACKGROUND: Over the past two decades, our group has conducted five multicenter trials focusing on first-line systemic therapy for patients with advanced pancreatic cancer. The current pooled analysis was designed to evaluate prognosis over time and the impact of clinical characteristics on survival. PATIENTS AND METHODS: Individual patient data were derived from five prospective, controlled, multicenter trials conducted by the 'Arbeitsgemeinschaft Internistische Onkologie' (AIO): 'Gem/Cis', 'Ro96', 'RC57', 'ACCEPT' and 'RASH', which recruited patients between December 1997 and January 2017. RESULTS: Overall, 912 patients were included. The median overall survival (OS) for all assessable patients was 7.1 months. OS significantly improved over time, with a median OS of 8.6 months for patients treated from 2012 to 2017 compared with 7.0 months from 1997 to 2006 [hazard ratio (HR) 1.06; P < 0.004]. Eastern Cooperative Oncology Group performance status (HR 1.48; P < 0.001), use of second-line treatment (HR 1.51; P < 0.001), and Union for International Cancer Control (UICC) stage (III versus IV) (HR 1.34, P = 0.002) had a significant impact on OS. By contrast, no influence of age and gender on OS was detectable. Comparing combination therapy with single-agent chemotherapy did not demonstrate a survival benefit, nor did regimens containing epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as afatinib or erlotinib, compared with chemotherapy-only arms. Patients with early-onset pancreatic cancer (age at study entry of ≤50 years, n = 102) had a similar OS compared with those >50 years (7.1 versus 7.0 months; HR 1.13; P = 0.273). The use of a platinum-containing regimen was not associated with better outcomes in patients with early-onset pancreatic cancer. CONCLUSIONS: Within this selected group of patients treated within prospective clinical trials, survival has shown improvement over two decades. This effect is likely attributable to the availability of more effective combination therapies and treatment lines, rather than to any specific regimen, such as those containing EGFR-TKIs. In addition, concerning age and sex subgroups, the dataset did not provide evidence for distinct clinical behavior.

Influence of mRNA expression of epiregulin and amphiregulin on outcome of patients with metastatic colorectal cancer treated with 5-FU/LV plus irinotecan or irinotecan plus oxaliplatin as first-line treatment (FIRE 1-trial).

Our aim was to investigate the impact of EREG and AREG mRNA expression (by RT-qPCR) in patients with metastatic colorectal cancer (mCRC). In addition, epidermal growth factor receptor (EGFR) expression (by immunohistochemistry) as well as RAS-and PIK3CA-mutations (by pyrosequencing) were assessed. Tumors of 208 mCRC patients receiving 5-fluorouracil/leucovorin plus irinotecan (FUFIRI) or irinotecan plus oxaliplatin (mIROX) within the FIRE-1 trial were analyzed for mutations. Molecular characteristics were correlated with response, progression-free survival (PFS), overall survival (OS). mRNA expression was evaluated using ROC-analysis in 192 tumors (AREG high n = 31 vs. low n = 161; EREG high n = 89 vs. low n = 103). High versus low AREG expression was associated with PFS of 10.0 versus 8.0 months (HR = 0.62, 95% CI: 0.402-0.940, p = 0.03) and OS of 24.6 versus 18.7 months (HR = 0.72, 95% CI: 0.476-1.078, p = 0.11). High versus low EREG expression correlated with prolonged PFS (9.4 vs. 6.8 months, HR = 0.62, 95% CI: 0.460-0.846, p = 0.002) and OS (25.8 vs. 15.5 months, HR = 0.48, 95% CI: 0.351-0.657, p < 0.001). The positive prognostic effect of high EREG expression was confirmed in a multivariate analysis and was neither affected by EGFR expression nor by mutations of RAS- and PIK3CA-genes. EREG expression appears as an independent prognostic marker in patients with mCRC receiving first-line irinotecan-based chemotherapy.

A multicentre phase II study of docetaxel plus cisplatin for the treatment of advanced gastric cancer.

BACKGROUND: The optimum regimen for advanced gastric cancer requires definition. This multicentre phase II study evaluated docetaxel-cisplatin combination in advanced gastric cancer. METHODS: Chemotherapy-naive patients with locally advanced or metastatic disease received docetaxel plus cisplatin (75/75 mg/m(2)) every 21 days for up to 9 cycles. Endpoints included tumour response, time to progression, overall survival and toxicity. RESULTS: Of 113 patients recruited, 88 were completely evaluable. The median age was 58 years, and most patients had metastatic disease. The overall response rate was 29.6%. Five patients (5.7%) achieved a complete response and 21 patients (23.9%) had a partial response. Tumour control, including stable disease, was achieved in 57 patients (64.8%). The median time to progression and median overall survival time was 4.8 and 8.7 months, respectively. The major toxicity was haematological: 37.5% of patients experienced grade 3-4 neutropenia, whereas febrile neutropenia was observed in only 2% of patients. CONCLUSION: Docetaxel-cisplatin was active with a predictable and manageable toxicity profile.

Second-line chemotherapy with pemetrexed after gemcitabine failure in patients with advanced pancreatic cancer: a multicenter phase II trial.

BACKGROUND: A standard second-line chemotherapy regimen has yet to be defined for patients with gemcitabine (Gem)-refractory advanced pancreatic cancer (PC). PATIENTS AND METHODS: In this multicenter phase II trial, patients with unresectable or metastatic PC who had progressed on single-agent Gem or a Gem-containing regimen received pemetrexed 500 mg/m(2) as a 10-min infusion every 3 weeks until disease progression or occurrence of unacceptable toxicity. The primary end point was the 3-month survival rate. RESULTS: A total of 192 treatment cycles were given to 52 patients. The overall response rate was 3.8% (two partial responses); 10 patients (19.2%) experienced stable disease, nine of them for >12 weeks. At least one CA 19-9 reduction > or =50% occurred in 12 patients (23.1%). The 3-month survival rate was 75% (95% confidence interval 63.2% to 86.8%), the median time to tumor progression was 7 weeks (range 1-62 weeks) and the median overall survival time was 20 weeks (range 1-84 weeks). Grade 3/4 hematological toxic effects included (percent of patients): neutropenia (17.3%), thrombocytopenia (5.8%) and anemia (3.8%). The most frequent non-hematological toxic effects were diarrhea, nausea and stomatitis/pharyngitis (23.1% each). CONCLUSION: Pemetrexed is a safe treatment option with moderate activity in patients with advanced PC after failure of Gem.

Protracted infusional 5-fluorouracil plus high-dose folinic acid combined with bolus mitomycin C in patients with gastrointestinal cancer: a phase I/II dose escalation study.

The aim of this study was to define the maximum tolerated dose (MTD) of bolus mitomycin C (MMC) in combination with 24 h-continuous infusion of 5-flourouracil (FU) plus folinic acid, and to assess the toxicity and activity in patients with previously treated colorectal and gastric cancer. Escalating doses of MMC starting from 6 mg m(-2) in 2 mg m(-2)-steps to a maximum of 10 mg m(-2) were applied on days 1 and 22, given to fixed doses of 5-FU (2.600 mg m(-2)) as 24 h infusion and folinic acid 500 mg m(-2) prior to 5-FU weekly for 6 weeks. At least three patients were treated at each dose level. A total of 16 patients have been included in the phase I study. At the highest dose level (MMC 10 mg m(-2)), grade III thrombocytopenia, dyspnoea, mucositis and diarrhoea were observed in one patient each (17 %). In the phase II study 45 patients, 33 with colorectal cancer and 12 with gastric cancer, 23 patients after failure of first- and 22 patients after at least second-line or subsequent chemotherapy have been treated. Seven partial responses (PR) were registered (16%), one (3%; CI(95%), 0-16) in colorectal and six (50%; CI(95%), 21-79%) in gastric cancer patients. In all, 17 (38%) achieved disease stabilisation, 15 colorectal (45%, CI(95%), 28-64%) and two gastric cancer patients (17%; CI(95%), 2-48%). The median progression-free survival was 3.1 months (range, 0.9-9.1) in colorectal and 4.6 months (range, 0.7-12.4) in gastric cancer. The median overall survival time was 6.6 months (range, 1.9-15.6) in colorectal and 7.1 months (range, 1.7-20.8) in patients with gastric cancer. This regimen was considered to be safe and well tolerated for pretreated patients with gastrointestinal adenocarcinoma. In gastric cancer,MMC plus infusional 5-FU/folinic acid may be a potential second-line regimen with promising antitumour activity.

Phase II study of weekly paclitaxel plus 24-h continuous infusion 5-fluorouracil, folinic acid and 3-weekly cisplatin for the treatment of patients with advanced gastric cancer.

The aim of this study was to evaluate the toxicity and efficacy of combination chemotherapy with weekly 24-h continuous infusion of 5-fluorouracil (5-FU)/folinic acid, weekly paclitaxel and 3-weekly cisplatin in patients with unresectable, locally advanced or metastatic gastric adenocarcinoma. Between November 1999 and November 2001, 29 chemotherapy-naive patients (13 male and 16 female) with a median age of 56 years (range 22-72) were consecutively enrolled at three centers. 5-FU 2 g/m2 was given weekly over 24 h i.v. preceded by folinic acid 500 mg/m2 as a 2-h infusion. Paclitaxel 80 mg/m2 was administered as a 1-h infusion weekly and cisplatin 50 mg/m2 as 1-h infusion on days 8 and 29. Six weeks of therapy (days 1, 8, 15, 22, 29 and 36) followed by 1 week of rest was considered one cycle. A median of 3 cycles (range 1-5) was administered to 29 patients with a total of 73 cycles applied. All patients were assessable for toxicity and survival, 28 patients were assessable for response (one patient received less than one complete cycle and could not be evaluated for response). Four patients (14%) obtained a complete response and 10 patients (34%) a partial response (overall response rate 48%, 95% CI 29-68%). Seven patients (24%) had stable disease. Seven patients (24%) had progressive disease during or within 4 weeks after treatment. The median progression-free and overall survival times were 8 months (range 1-23) and 11 months (range 1-23), respectively. Overall toxicity was acceptable. Hematological toxicity was favorable with only one patient (3%) experiencing WHO grade 3/4 leukocytopenia and one patient (3%) WHO grade 3/4 anemia. Non-hematologic WHO grade 3/4 toxicities included alopecia in 19 (66%), nausea/vomiting in six (21%), diarrhea in six (21%), neurotoxicity grade 3 in three (10%) and infection in three (10%) patients. A total of 42 applications (10%) (range 0-5) had to be postponed and dose reductions of at least one drug was necessary in 37% of applications. In three patients (10%) treatment was stopped because of toxicity. All patients were treated on an outpatient basis. Thus, the combination of weekly paclitaxel, cisplatin and continuously infused 5-FU/folinic acid appears to be a highly active regimen for the treatment of patients with advanced gastric cancer. Compared with our previous experience with the same combination of drugs but using paclitaxel at 175 mg/m2 given every 3 weeks, the protocol with weekly application of paclitaxel 80 mg/m2 shows a reduced incidence of hematologic toxicity, particularly leukopenia. Other organ toxicities apart from a slightly higher incidence of peripheral neuropathy were comparable between the two treatment protocols. Efficacy with a response rate of 50% was well preserved by this weekly regimen.

A phase II study of paclitaxel, weekly, 24-hour continous infusion 5-fluorouracil, folinic acid and cisplatin in patients with advanced gastric cancer.

To evaluate the toxicity and efficacy of combination chemotherapy with paclitaxel, cisplatin and 24 h continuous infusion of 5-FU/folinic acid in patients (pts) with unresectable, locally advanced or metastatic gastric adenocarcinoma. Forty-five chemotherapy-naive pts (28 male and 17 female) with a median age of 60 years (range 35-74) were enrolled. 5-FU 2 g/m2 was given weekly over 24 h i.v. preceded by folinic acid 500 mg/m2 as a 2 h infusion. Paclitaxel 175 mg/m2 was administered as a 3 h-infusion on days 1 and 22 and cisplatin 50 mg/m2 as 1 h infusion on days 8 and 29. Six weeks of therapy (days 1, 8, 15, 22, 29, 36) followed by 2 weeks rest were considered one cycle. A median of 3 cycles (range 1-4) were administered to 45 pts assessable for response, survival and toxicity. Five pts (11%) obtained a CR and 18 pts (40%) a PR (ORR 51%; 95% CI: 35.8-66.3%). Responses were achieved in the liver, lymph nodes, lungs and at the site of the primary tumour. Nine pts (20%) had stable disease. Thirteen pts (29%) were considered to have failed treatment, 8 pts (18%) due to progressive disease and 5 pts (11%) who did not receive one complete cycle of therapy due to acute non-haematologic toxicity. The median progression-free and overall survival times were 9 months (range 1-36+) and 14 months (range 2-36+), respectively. Neutropenia WHO III(o)/IV(o) occurred in 7 pts (15%) with only 1 pt having grade IV. Additional non-haematologic WHO III(o)/IV(o) toxicities included nausea/vomiting in 5 (11%), alopecia in 22 (49%), and diarrhoea in 1 patient each (2%). Dose reductions or treatment delays were necessary in 8 pts (17%), mainly due to neutropenia. All pts were treated on an outpatient basis. The combination of paclitaxel, cisplatin and continuously infused 5-FU/folinic acid appears to be a highly active regimen for the treatment of pts with advanced gastric cancer. While the overall acceptable toxicity allows its use in the palliative setting, it may also be an attractive option to be tested for neoadjuvant or adjuvant treatment.

Mitomycin C continuous infusion as salvage chemotherapy in pretreated patients with advanced gastric cancer.

UNLABELLED: Our purpose was to evaluate the safety and therapeutic activity of continuously infused mitomycin C in patients with recurring or progressive metastatic gastric cancer following first-line chemotherapy. Patients were treated with mitomycin C 20 mg/m2 i.v. over a time period of 120 h followed by a 3-week rest period. All patients received prednisone 50 mg p.o. prophylactically for 5 days to prevent hemolytic uremic syndrome and pulmonary side effects. Twenty-two consecutively enrolled patients were assessable for toxicity and 20 for response evaluation completing at least one full course of chemotherapy (two patients evaluable but not measurable). PATIENT CHARACTERISTICS: median age: 63 years (39-76); Sex (M/ F): 13/9; median Karnofsky status: 70% (50-100%); resection of primary tumor n = 12 (55%); sites of metastases: liver n = 17 (77%), locally advanced n = 10 (45%), peritoneum n = 13 (59%), lungs n=5 (23%), bone n=3 (14%) and lymph nodes n=14 (64%). Previous chemotherapy regimens: bolus 5-FU/folinic acid n=6 (27%), ELF n=4 (18%), EAP n=3 (14%) and continuous 5-FU/folinic acid/cisplatin/paclitaxel n=9 (41%). In 20 evaluable patients one complete and five partial remissions were observed; overall response rate 30.0% [95% confidence interval (CI): 9.1-50.9%] with a median response duration of 2.1 months (range: 2-6). The median survival was 3.6 months (95% CI: 2.1-6.0) resulting in a 6-month survival rate of 30% since start of mitomycin C. WHO grade III/IV mucositis, diarrhea and fever/infection occurred in 9% of patients each. Cumulative thrombo- and leukocytopenia (WHO grade II/IV) were observed in four and two patients, respectively. Treatment had to be stopped early in two patients. No severe renal dysfunction, pulmonary toxicity or evidence of hemolytic uremic syndrome was observed. Fatigue during the 120 h infusion of mitomycin C was common (11 of 22 patients). We conclude that continuous infusion of mitomycin C is feasible on an outpatient basis, revealing an acceptable toxicity. Mitomycin C demonstrates single-agent activity in pretreated gastric cancer, but has only limited efficacy following cisplatin/paclitaxel-based first-line chemotherapy.

Comparison of the tumor associated proteases cathepsin D (CATH D) and urokinase-type plasminogen activator (uPA) in cytosols of human breast cancer patients.

As a matter of routine, prepared cytosols of human primary breast cancer specimens (n = 230) are analysed for both CATH D and hormone receptor status (ER,PR). Retrospectively, uPA was determined in the samples. The selection criterion for the retrospective analysis was the possibility of a longitudinal follow-up of the patients. All tumor stages were included, but the main emphasis was on lower tumor stages (T1, and T2) as well as nodal negative stages (N0). The results of the hormone receptor status (ER,PR) were: ER+PR+ 66.37%; ER+PR- 10.18%, ER-PR+ 10.18%, ER-PR- 13.27%. The CATH D results ranged from 5 to 246 pmol/mg protein. 30.97% of these results rose above 50 pmol/mg protein (positive), 42.48% were below 35 pmol/mg protein (negative). The uPA results ranged from 0.05 to 3.74 ng/mg protein. 27.43% of the uPA results rose above 0.71 ng/mg protein (positive), 58.85% were below 0.53 ng/mg protein (negative). Raised results of uPA are distinct in the higher tumor stages (T1N0 > T2N0 > T2N1 > T4Nx). Although the CATH D and uPA measurements showed similar results (positive/negative distribution) in the general survey, the confirmity of both factors is rather limited if it is focused to single cases. Between CATH D and uPA there was a confirmity of 50% (T1N0) of 45.5% (T2N0) respectively in the range of positive results, and there was a confirmity of 60.3% (T1N0) and 65.8% (T2N0), respectively, in the range of negative results. Differences were seen in 19.2% (T1N0) and 22.7% (T2N0), respectively, in the range of positive results, and in 20.6% (T1N0) in 1508% (T2N0), respectively, in the range of negative results. The prospectively diagnostic value of these is still under observation.

A phase II trial of paclitaxel and weekly 24 h infusion of 5-fluorouracil/folinic acid in patients with advanced gastric cancer.

A phase II trial was performed to evaluate the efficacy and toxicity of the combination of paclitaxel and 5-fluorouracil (5-FU)/folinic acid in patients with advanced gastric carcinoma. Twenty-two patients (six female and 16 male) with advanced or metastatic disease were enrolled. None of them had received prior chemotherapy. Paclitaxel was administrated as a 3 h infusion of 175 mg/m2 at days 1 and 22, 5-FU 2000 mg/m2 i.v. over 24 h and folinic acid 500 mg/m2 i.v. 2 h prior to 5-FU weekly from days 1 to 36. Seven patients (32%) had partial remissions including the lungs, skin, lymph nodes and locally advanced primary tumor. The median overall survival was 11 months (range 1-17+) and the median progression-free interval was 8 months (range 1-13+). Neutropenia (WHO grade III/IV) occurred in 14% of patients. Other main toxicities were alopecia in 45%, fever/infection in 9%, and nausea/vomiting and diarrhea in 5%. In conclusion, the combination of paclitaxel and continuously infused 5-FU/folinic acid appears to be an active regimen for advanced gastric carcinoma with a remission rate comparable to ELF or FAMtx. The moderate toxicity allows treatment on an outpatient basis.

Paclitaxel and weekly 24-hour infusion of 5-fluorouracil/folinic acid in advanced gastric cancer.

The current phase II study evaluates the safety and efficacy of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and 5-fluorouracil (5-FU) plus folinic acid in patients with advanced gastric cancer. Paclitaxel 175 mg/m2 was given intravenously over 3 hours on days 1 and 22; folinic acid 500 mg/m2 given intravenously over 2 hours followed by 5-FU 2,000 mg/m2 given intravenously over 24 hours was administered on days 1, 8, 15, 22, 29, and 36. Six weeks of treatment were considered one cycle, and each cycle was followed by 2 weeks off treatment. Twenty-two patients (six women and 16 men) with advanced/metastatic gastric cancer were entered on trial. All patients are evaluable for response and toxicity. None had received prior chemotherapy. Radiologically metastatic sites included gastric lymph nodes (64%), liver (36%), lungs (18%), peritoneum (18%), bone (9%), and skin (5%). No complete responses were observed. Seven patients (32%; 95% confidence interval, 12% to 52%) had a partial response. Sites of partial responses included the lungs, skin, lymph nodes, and locally advanced tumor. Twelve patients (55%) had stable disease and three (14%) had disease progression. At a median follow-up of 12 months (range, 1 to 17+ months), the median overall survival for all patients was 11 months (range, 1 to 17+ months; 95% confidence interval, 6.8 to 18.2) and the median progression-free interval was 8 months (range, 1 to 13+ months; 95% confidence interval, 4.7 to 9.8). Severe nonhematologic toxicities were alopecia (45%), fever/infection (9%), diarrhea (5%), and nausea/vomiting (5%). Grade 3/4 neutropenia occurred in three patients (14%). In summary, paclitaxel given every 3 weeks in combination with once-weekly, 24-hour continuous infusions of 5-FU/folinic acid is active in advanced gastric cancer and appears to achieve response rates comparable to regimens like etoposide/folinic acid/5-FU or 5-FU/doxorubicin/methotrexate. The toxicity of this new combination is moderate and allows treatment in an outpatient setting. Ongoing studies are evaluating the activity of paclitaxel combined with weekly continuous infusions of 5-FU/folinic acid with or without cisplatin.

Coronary heart disease mortality, morbidity, and case fatality in five east and west German cities 1985-1989. Acute Myocardial Infarction Register Teams of Augsburg, Bremen, Chemnitz, Erfurt, and Zwickau.

Cardiovascular mortality (CVD; International Classification of Diseases [ICD] 390-458) is higher in East than in West Germany, but the differences in official coronary heart disease mortality (CHD; ICD 410-414) are not so pronounced. The aim of this study was to validate the official mortality statistics based on the five German AMI registers and to analyze whether these mortality differences are due to differences in the attack rates of acute myocardial infarction (AMI) or to differences in the 28-day case fatality rates. This comparison includes the MONICA study cities of Augsburg and Bremen, both in West Germany, as well as the cities of Chemnitz, Erfurt, and Zwickau in East Germany (former the German Democratic Republic). The rates were calculated on the basis of all MONICA cases of definite AMI or coronary death aged 35 to 64 years occurring in the respective study populations between 1985 and 1989. All study populations except women in Augsburg showed higher coronary death rates compared to the rates based on the official cause of death statistics (ICD 410-414), but this difference was significant only for men in Chemnitz. In men there were no significant differences in the register-based coronary death rates between these urban areas (160/100,000 in Zwickau to 170/100,000 in Chemnitz) nor in the AMI attack rates (327/100,000 in Augsburg to 363/100,000 in Chemnitz), and consequently no significant center differences in the overall 28-day case fatality. However, the prehospital case fatality was significantly higher in Erfurt (34%) than in Bremen (27%). There were no significant differences in the AMI attack rates in women as well (60/100,000 in Chemnitz to 70/100,000 in Bremen and Erfurt), but the overall 28-day case fatality showed a clear gradient from the East (61-71%) to the West German cities (48-56%) and therefore also the register-based coronary death rates (38-50/100,000 and 34-38/100,000, respectively). However, the higher 28-day case fatality in women found in the MONICA registers in East compared to West Germany is not reflected in the CHD mortality statistics because of a stronger underestimation of the official mortality rates and in East than in West Germany, in particular in women. Nevertheless, the total mortality rates and in most cases also the CVD mortality rates were in women significantly higher in the East German compared to the West German cities. The East German official preunification CHD mortality data cannot be used for national and international comparisons. The results of the MONICA AMI registers in East and West Germany indicate, furthermore, the need to improve coronary care in women in the eastern part of the country. Nevertheless, because of the relatively high AMI attack rate in both parts of Germany primary prevention must generally be intensified.

[Antineoplastic chemotherapy in metastatic Wilm's tumor]. / Antineoplastische Chemotherapie bei metastasiertem Wilmstumor.

Wilms tumors may, rarely, also occur in adulthood. A 32-year-old male who, following the removal of a Wilms tumor, developed recurrent disease and metastases to the lungs and liver, was treated with a polychemotherapeutic regimen. Primarily, this was based on the protocol usually applied in children that comprises a combination of actinomycin D, vincristine, and adriamycin. Treatment initially achieved a six-month partial remission. Further treatment became necessary when a recurrence again occurred, and resulted in a "no change" situation that lasted for two months. The subsequent deterioration of the patient prompted monotherapy with vincristine, resulting in a transient clinical improvement. The patient finally died 25 months and two weeks after chemotherapy was first initiated.

[The therapy of advanced breast carcinoma in men]. / Therapie des fortgeschrittenen Mammakarzinoms beim Mann.

Four men (mean age 50 [42-57] years) were treated for advanced carcinoma of the breast, two of them by chemotherapy alone. Survival time in the latter two after start of the chemotherapy was 5 and 8 months, respectively. The third patient received both hormone and chemotherapy from the start because of unfavourable prognostic criteria. For 15 months the tumour stage remained unchanged until the patient developed incomplete paraplegia which improved greatly after decompression laminectomy. This has been followed for four months by renewed hormonal and chemotherapy. The fourth patient received tamoxifen for seven months, with intrapleural administration of cytostatic agents and finally pleurectomy for recurrent malignant pleural effusions. For 4 months he has again been receiving hormonal and chemotherapy. These cases illustrate that if there are unfavourable prognostic criteria chemotherapy should be added to conventional hormone therapy.

[Variation in nocturnal blood pressure behavior in stage III (WHO) hypertension--a case report]. / Abweichungen des nächtlichen Blutdruckverhaltens bei Hypertonie vom Schweregrad III (WHO)-eine kasuistische Betrachtung.

In some cases of hypertensive men the authors obtained 24-hour blood pressure profiles by easy non-invasive technique (Mercury manometer) and under the usual atmosphere and activities of a hospital. The control Group, 32 normotensive men, showed a normal circadian blood pressure variability with systolic acrophases at 10.00 h and 16.00 h and a bathyphase around 3.00 h. The diastolic blood pressure had a smaller variability. One patient with essential hypertension stage II (WHO), case 1, kept the normal day-night rhythm. By case 2, a man with essential hypertension stage III (WHO), the authors refer to the possibility of considerable differences of blood pressure behaviour during the night in cases of severe hypertension in contrary to normal blood pressure variability. After a supplementary fourth medication this patient showed a significant decrease of blood pressure during the night. Nevertheless he kept his acrophase at night. The recording of day-night profiles of blood pressure seems to be useful in relation to the judgement of classification of severity, of the mode of anti-hypertensive medication and of the success in therapy.

[Immunomodulation with apheresis technics]. / Immunmodulation durch Apheresetechniken.

The use of apheresis therapy (plasmapheresis/plasmafiltration or cytopheresis) was successful in numerous immunological diseases. Autoimmune and immune complex diseases as well as paraproteinemias with hyperviscosity syndrome (M. Waldenström, plasmocytoma) are the main indications. The several modifications of apheresis and its indications are outlined, and possible immune regulatoric effects of apheresis therapy are discussed. Finally this paper refers to beginning changes from unspecific to more selective methods of apheresis (cascade filtration, cryofiltration, immunoadsorption, enzymatic degradation, continuous electrophoresis) and its significance for clinical and experimental immunology.

[Plasma exchange therapy (plasmapheresis/plasmafiltration). II. Indications and complications]. / Plasmaaustauschtherapie (Plasmapherese/Plasmafiltration). Teil II. Indikationen--Komplikationen.

On the basis of an extensive study of references as well as of own experiences the present state of the plasma exchange therapy, its success, problems and tendencies are represented. In the 1st part the essential modifications of the technique (plasmapheresis/plasma filtration), problems of anticoagulation, kind and quantity of the substitution as well as tendencies to more specific separation methods are explained. The 2nd part gives a survey of all essential indications (Goodpasture's syndrome, myasthenia gravis, hyperviscosity syndrome, lupus erythematodes visceralis, intoxications) and shows the main complications.

[Plasma exchange therapy (plasmapheresis/plasma filtration). I. Technic]. / Plasmaaustauschtherapie (Plasmapherese/Plasmafiltration) Teil I. Technik.

With the help of an extensive study of literature as well as of own experiences the technical aspects of the plasma exchange therapy are described. Issuing from their hitherto existing course of the development and corresponding to their present significance the essential signs of the nowadays usual modifications (plasmapheresis by means of sedimentation in transfusion containers or by means of blood cell separator as well as plasma filtration) are explained. The discussion of problems of anticoagulation, the kind and quantity of substitution solutions as well as of developmental tendencies to more specific separation techniques leads over to the survey of essential indication areas (part II).

[Pheochromocytoma and shock]. / Phäochromozytom und Schock.

In phaechromocytomas with predominant beta-adrenergic activity in a short time develop hypovolaemia and shock due to capillary transudation and profuse sweating. On the basis of an own observation the following symptoms may be summarized: signs of centralisation such as cold, pale, sweat-covered skin, cool extremities in increased nuclear temperature, clear decrease of the blood pressure, tachycardia, arrhythmia, signs of the left heart insufficiency and considerable changes of the ECG as an expression of a catecholamine-induced cardiomyopathy, strong abdominal pains, strong feeling of thirst in isotonic dehydration, oliguria and metabolic acidosis. In patients with shock syndrome of unclear etiology should also be thought of a phaeochromocytoma after exclusion of the most frequent causes.