Prediction of necrosis after chemotherapy of advanced germ cell tumors: results of a prospective multicenter trial of the German Testicular Cancer Study Group

PURPOSE: We evaluated the prognostic parameters of necrotic residual tumors after chemotherapy of advanced germ cell tumors to improve on the current indications for surgery. MATERIALS AND METHODS: Between January 1996 and January 2000, in 8 centers of the German Testicular Cancer Study Group, preoperative parameters were assessed to predict necrosis in the residual tumors of 261 patients with retroperitoneal residual tumor resection after first (92%) and second line (8%) chemotherapy. RESULTS: Of 232 evaluable patients 39 had pure seminoma and 5 had viable cancer (1 with seminoma) in the residual tumor. Of the remaining 193 patients with nonseminoma 35% had necrosis, 34% teratoma and 31% had viable carcinoma in the residual tumor. After multivariate analysis and exclusion of patients with seminoma, the 3 parameters independently predictive of necrosis were alpha-fetoprotein before chemotherapy less than 20 ng/ml, and tumor volume before and after chemotherapy. A mathematical model to predict necrosis yielded a test accuracy of 75%, a sensitivity to predict necrosis of 52% and a specificity of 87%. CONCLUSIONS: Patients with pure seminoma should not undergo residual tumor resection because 97% of patients who received adequate chemotherapy were found to have no residual seminoma. In cases of nonseminoma alpha-fetoprotein values before chemotherapy less than 20 ng/ml and a high percentage of shrinkage during chemotherapy reliably predicted only 19% of cases of necrosis. Therefore, this model is clinically irrelevant and patients with minimal residual disease should undergo surgery. New methods are necessary to improve the preoperative selection of patients after chemotherapy.     

Comparison of two-dimensional echocardiographic and angiographic findings in arrhythmogenic right ventricular dysplasia

Comparison of 2-dimensional (2-D) echocardlographic and right ventricular (RV) angiographic findings was performed in 10 patients with arrhythmogenic RV dysplasia. Diagnosis was based on accepted electrocardiographic and angiographic criteria. Nine patients underwent invasive electrophysiologic study, which confirmed RV source of ventricular tachycardia (VT) In 7. Biopsy findings of RV dysplasla were available in 3 patients. Two-dimensional echocardiography and angiography corresponded closely when diffuse RV enlargement and hypoldnesla were present. Such diffuse findings were not invariably present. Localized abnormalities consisting of bulging or sacculation of the RV wall were noted by both techniques, even in the absence of diffuse changes. Echocardiographic evidence of localized disease predicted the presence of similar lesions at angiography, but agreement as to specific location was poor. Subjectivity In interpreting subtle RV abnormalities by either technique and the inherent differences in information provided by the 2 methods probably account for the inconsistencies. In the patient with suspected arrhythmogenic RV dysplasia, 2-D echocardiographic evidence of diffuse RV enlargement, otherwise unexplained, strongly supports the diagnosis and angiography may be avoided. Isolated local changes seen by echocardiography should increase suspicion of RV dysplasia, but complementary angiographic study is warranted.     

Unsuspected gallbladder carcinoma--the CAE-S/CAMIC registry

INTRODUCTION: Results of earlier surveys raised the prospect that laparoscopic surgical procedures may specifically increase the risk of port wound metastasis and generally of tumour cell seeding if at the time of operation an unsuspected gallbladder cancer existed. Other observations lead to presume that laparoscopic technique could deteriorate the prognosis of gallbladder cancer. These assumptions are going to be verified by the CAES/ CAMIC-registry. MATERIAL AND METHOD: The Workgroup Surgical Endoscopy (CAE) of the German Society of Surgery has started 1997 a registry of all cases of cholecystectomy--laparoscopic as well open--with a postoperative incidental finding of a gallbladder carcinoma. The aim of our registry is to compare the prospectively collected follow up data on the outcome of these patients and to answer the question whether laparoscopic cholecystectomy affects the course and the prognosis of patients with unsuspected gallbladder cancer. RESULTS: Until now 142 cases of incidental gallbladder cancer following laparoscopic and 79 cases following open cholecystectomy as well as 24 cases after intraoperative conversion to the open procedure have been recorded. The median follow up runs up to 27 (1-69) months. Following laparoscopic primary procedure we registered 10 port site metastases (7 %), following open primary procedure 4 (5.1 %) wound recurrences. The total recurrence rate at the moment is about 27 % after laparoscopic treatment and 31 % for conventionally operated patients. 70 of the 245 patients underwent a second radical procedure after diagnosis of gallbladder carcinoma. A postoperative combined radio- and chemotherapy was undertaken in 4 cases, a chemotherapy alone in 14 cases. 64 patients already died due to the underlining disease. DISCUSSION: At the present, after a median follow up of 27 months, the incidence of abdominal wall recurrences is very similar following laparoscopic and conventional procedure (7 % vs. 5.1 %). The total incidence of recurrences is at the moment slightly higher following open cholecystectomy (31 % vs. 27 %). The access technique, open or laparoscopic, doesn't seem to influence the prognosis of unsuspected gallbladder carcinoma. Until now we could not find disadvantages for the laparoscopically operated group.     

Insufficiency risk of esophagojejunal anastomosis after total abdominal gastrectomy for gastric carcinoma

Background The outcome and quality of surgical treatment in gastric cancer are closely associated with specific postoperative morbidity and mortality, in addition to an oncosurgically adequate resection status. In this context, a preventive concept of decreasing the insufficiency rate of esophageal anastomosis may have a great impact.Method Over a time period of 12 months (from 1 January 2002 to 31 December 2002), 1,199 patients (from 80 East German hospitals) with gastric carcinoma, carcinoma of the esophagogastral junction, or gastrointestinal stroma tumor (GIST) were enrolled in this prospective multicenter observational study with the aim of evaluating their early postoperative outcome. By means of a logistic regression analysis, independent variables, which alter significantly the healing of esophagojejunal anastomosis, were determined; in addition, their clinical impact on preventive management to lower the insufficiency rate of esophageal anastomosis was investigated.Results In 1,139 patients, histological investigation revealed gastric carcinoma. Out of these patients, 1,031 subjects underwent surgical intervention (90.5%) and 891 individuals underwent resection (86.4%). In 813 patients, radical resection (subtotal resection and gastrectomy) was executed (78.9%), whereas in 726 cases, R₀ resection was achieved (81.5%). Gastrectomy was the preferred procedure in 649 patients, resulting in a gastrectomy rate of 62.9% relating to all patients who underwent operation (curative and palliative intention, 80.3% and 19.7%, respectively). The insufficiency rate of esophagojejunal anastomosis was 5.7% (37/649). Neither the comparison between the various procedures for the reconstruction of the esophagojejunal passage and anastomosing techniques after gastrectomy nor that between gastrectomies with curative and palliative intention revealed any significant difference. Dysphagia and gastric outlet syndrome due to a stenosis were determined as independent variables by a logistic regression analysis of all preoperative and intraoperative variables. In all patients with gastric carcinoma, both parameters were recorded in 9.9% (113/1,139) and 6.7% (76/1,139), respectively.Conclusion Dysphagia and gastric stenosis, which significantly influence the healing of esophagojejunal anastomosis after gastrectomy, are considered characteristics of an advanced tumor growth and a pretherapeutic lack of an adequate nutrition. This emphasizes the necessity of an early diagnosis of gastric cancer in order to lower perioperative morbidity. In addition, dysphagia is commonly associated with an obstruction of the upper gastrointestinal tract, which can lead to nutritional deficits, and thus deserves specific care during preventive management.     

Difference in development of medullary thyroid carcinoma among carriers of RET mutations in codons 790 and 791

Objectives Hereditary medullary thyroid carcinoma (MTC) is caused by germ‐line mutations in the RET proto‐oncogene. Our study addresses the difference in development of MTC between rare mutations in RET codons 790, 791 and 804. Design We evaluated tumour stage, calcitonin levels, biochemical cure rates and associated endocrinopathies in 153 German/Austrian patients with RET 790 (n = 47), 791 (n = 56) and 804 mutations (n = 50), divided into index‐ and screening groups. Results Age at diagnosis in index‐patients did not differ significantly among the three codon groups (medians of 57, 61 and 53 years). Tumour stage at diagnosis was significantly less advanced with codon 791 (n = 22) than 790 (n = 16) and 804 (n = 16) mutations (P = 0·001). In screening patients, age at diagnosis did not differ significantly among the three groups (medians 19, 24 and 32 years). Tumour stage at diagnosis was also significantly less advanced with codon 791 (n = 34) than 790 (n = 31) and 804 (n = 34) (P = 0·032). Preoperative basal calcitonin levels were significantly lower in codon 791 carriers compared to codon 790 carriers, and cure rates were significantly higher in both index (75%vs. 31%; P = 0·03) and screening patients (100%vs. 75%; P = 0·015). Additional endocrinopathies were observed only with codon 791 carriers (four pheochromocytomas and two hyperparathyroidism). Conclusion There is a significant difference in MTC development with less extensive C‐cell disease, higher cure rate and more frequent additional endocrinopathies in carriers of RET codon 791 mutations compared with carriers of codons 790 and 804 mutations. This information should be considered when age of prophylactic thyroidectomy is discussed.     

Chemotherapy for mobilisation of Ph-negative progenitor cells from patients with CML: impact of different mobilisation regimens

Mobilised peripheral blood stem cells are widely used for autografting in patients with chronic myeloid leukaemia (CML) and it is generally thought that a high proportion of Ph-negative progenitor cells in the graft is desirable. We report here the results of 91 stem cell mobilisations performed with various chemotherapy regimens followed by G-CSF. We show that mobilisation of Ph-negative cells is possible after diagnosis as well as in advanced stages of the disease. The yield of Ph-negative cells is highly dependent on the chemotherapy regimen: while the combination of idarubicin and cytarabin for 3-5 days (IC3-5) mobilised Ph-negative cells in most patients, high-dose cyclophosphamide was ineffective. Mobilisation of Ph-negative progenitor cells after IC3 was at least as effective as after IC5; however, less apheresis sessions were required, and toxicity was much reduced after IC3. Compared to historical controls, IC was equally effective as the widely used ICE/miniICE (idarubicin, cytarabin, etoposide) protocol. No correlation was found between graft quality and the cytogenetic response to subsequent treatment with interferon-alpha. We conclude that IC3 is an effective and well-tolerated regimen for mobilising Ph-negative cells that compares well with more aggressive approaches such as IC5 and ICE/miniICE.     

Towards a pathogenesis-oriented therapy of acute myeloid leukemia

Genetic and molecular techniques have provided increasing insights into the biology of acute myeloid leukemia (AML). These investigations showed that AML is not a homogeneous disease but a heterogeneous group of biologically different subentities. These subentities are currently primarily defined by cytogenetics by which three main subgroups can be discriminated: AML with balanced translocations, AML with unbalanced aberrations and AML without cytogenetically detectable aberrations. Within the latter group molecular alterations are identified in more than half of cases such as NPM mutations, FLT3 mutations, MLL duplications and mutations of CEBP-alpha. The clinical meaning of these findings is illustrated by substantial differences in response to therapy and long-term outcome. As demonstrated by the recent multicenter trial of the German AML Cooperative Group (AMLCG) and other studies intensification of induction therapy may improve the results in distinct subtypes but fails to do so in others. Therefore, new strategies need to be explored which incorporate the knowledge about the biology of AML to develop biology adapted treatment strategies. This process has just begun and is predominantly determined by the availability of new agents and their evaluation in clinical phase I and II studies. A variety of targets are currently explored and some trials have yielded promising results already. The step towards a biology adapted treatment of AML is long and requires the combined efforts of researchers, clinicians and the pharmaceutical industry. The first steps towards this goal have been taken and give rise to the hope for more effective and more specific therapies of AML.     

Low acute hematological toxicity during chemotherapy predicts reduced disease control in advanced Hodgkin’s disease

Chemotherapy-treated patients with advanced Hodgkins disease (HD) differ considerably in acute hematotoxicity. Hematotoxicity may be indicative of pharmacological and metabolic heterogeneity. We hypothesized that low hematotoxicity might correlate with reduced systemic dose and thus reduced disease control. A total of 266 patients with advanced HD treated with cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP-ABVD) were analyzed (HD6 trial of the German Hodgkins Lymphoma Study Group). The reported WHO grade of leukocytopenia was averaged over chemotherapy cycles given and weighted with the reciprocal dose intensity of the corresponding cycle. The low and high toxicity groups were defined in retrospect as having had an averaged WHO grade of leukocytopenia 2.1 and >2.1, respectively. The independent impact of low hematological toxicity on freedom from treatment failure (FFTF) was assessed multivariately adjusting for the international prognostic score for advanced HD. The results were validated in two independent cohorts [181 patients treated with COPP-ABVD (HD9-trial) and 250 patients treated with COPP-ABV-ifosfamide, methotrexate, etoposide, and prednisone (IMEP) (HD6 trial)]. The 5-year FFTF rates were 68% for patients with high toxicity vs 47% for patients with low toxicity [multivariate relative risk (RR) 2.0, 95% confidence interval (CI) 1.4–3.0, p=0.0002]. Patients with low toxicity received significantly higher nominal dose (p=0.02) and dose intensity (p<0.0001). This finding was confirmed in both validation cohorts (multivariate RR 2.1, 95% CI 1.2–3.8, p=0.01 and RR 1.5, 95% CI 1.01–2.26, p=0.04, respectively). Patients with low hematotoxicity have significantly higher failure rates despite higher doses and dose intensity. Hematotoxicity is an independent prognostic factor for treatment outcome. This observation suggests a strategy of individualized dosing adapted to hematotoxicity.The authors listed above wrote this contribution on behalf of the German Hodgkins Lymphoma Study Group     

Isosorbide dinitrate spray as therapeutic strategy for treatment of chronic venous ulcers

Venous ulcers are the most common form of leg ulcers, which induce lesion because of the loss of substances deposited on the damaged skin. Isosorbide dinitrate is a vasodilator with effects on both arteries and veins and induces opening of vascular layers. The objective is to study the effects of isosorbide dinitrate-spray in patients with chronic venous ulcers. Forty-five patients of both sexes with chronic venous ulcers were randomized to receive isosorbide dinitrate or placebo sprays daily for 3 months. The ulcers were measured and clinical characteristics were taken every 15 days during the treatment. Patients treated with isosorbide dinitrate showed an improvement of the ulcerated area (71.29%) compared with patients treated with placebo (54.35%). The histopathological study indicated an increment in the number of hypertrophic and hyperplasic capillaries. Macroscopically, the isosorbide dinitrate-treatment showed the best results, but it was only during the first 6 weeks of treatment. Patients with chronic venous ulcer receiving isosorbide dinitrate spray showed improvement.