Biomedical subjects
Publications and source records attributed to R Klapdor.
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Our preliminary evaluation of a new monoclonal antibody-based assay for tissue polypeptide antigen (TPA) has shown it to be clinically equivalent to the polyclonal antibody-based assay for TPA. The new assay (TPA-M) employs three monoclonal antibodies to epitopes on cytokeratins 8, 18 and 19. This multicenter, multinational study included 266 patients with newly diagnosed carcinomas of the lung, breast, large bowel and urinary bladder. TPA values from the two assays were compared with three other cytokeratin markers (TPS, CYFRA 21-1 and TPACyk) and with the established reference markers for these malignancies (CEA and NSE for lung, CA 15-3 for breast, CEA and CA 19-9 for colorectal tumors). Analysis of receiver operating characteristic (ROC) curves in lung, colorectal and bladder cancer showed similar sensitivities for the two assays, ranging from 50% to 80% with a specificity of 95%. In breast cancer all the markers studied showed poor sensitivity. However, TPA determination by either method could discriminate advanced stage (stages III and IV) from early stage disease (stages 0 to II). TPA showed similar discriminating ability in bladder cancer. On the basis of the results obtained in our patient series, it seems that of the cytokeratin markers studied, TPA and TPA-M are the most sensitive and offer a wide range of clinical applications.
BACKGROUND: The aim of this study was to evaluate the TNM categories and histopathological grading as prognostic factors in mucoepidermoid carcinoma (MEC). In addition, the study was designed to provide baseline data on levels of tumor-associated antigens (TAA) in sera of MEC patients. MATERIALS AND METHODS: Fifty-nine patients with MEC of the salivary glands were evaluated. RESULTS: Reclassified TNM stage, at the time of initial diagnosis, varied considerably. In disease-free patients, none of the tested sera were TAA elevated above the cut-off levels. Our patients who died of tumor metastasis had all been classified as stage III or IV at the time of initial diagnosis. Distant metastases are rarely found even decades after surgical therapy. CONCLUSIONS: Long-term follow-up is recommended for patients with MEC of the salivary glands. TAA are not elevated in disease-free patients. The value of TAA in the monitoring of MEC patients remains to be evaluated in further studies.
UNLABELLED: The aim of this prospective study was to determine the role of FDG-PET in the follow up care of patients with pancreatic carcinoma in comparison with sonography, computed tomography and tumour marker levels. 19 patients were investigated, 9 patients with non-resectable tumour disease and 10 patients after resection of primary tumor. We found corresponding results in 15/19 patients, but in 2 patients additional metastases were detected. In another 5 patients of this group, PET results decisively influenced the further therapeutic procedure. In 2/19 patients only PET showed viable tumour tissue, in spite of negative findings in CT and sonography. In 2/19 patients we found false negative results with PET. One patient had increased blood glucose levels at the time of investigation, the other one was investigated shortly after locoregional chemotherapy. Compared to CA 19-9, PET investigation may also result in positive findings, in spite of non elevated CA 19-9 serum levels. CONCLUSION: PET has been shown as an effective tool also in the follow up care of patients with pancreatic cancer. In more than half of the patients PET offered important additional information to clinicians, resulting in a change of the therapeutic procedure. Especially before locoregional chemotherapy or in case of increased tumor marker levels without morphological substrate in US/CT PET with FDG seems to represent a valuable investigation.
In a prospective clinical study we examined the diagnostic procedures used in the preoperative diagnosis of colorectal cancer patients (n = 176) and the value of supplementation of standard diagnostic methods (clinical investigation, colonoscopy, barium enema, ultrasound, computer tomography) with a test for occult fecal blood (FOBT) and an expanded tumor marker panel (CA 19-9, TPS and CA 72-4 in addition to CEA) in the postoperative follow-up (n = 116, mean follow-up 21 months). Preoperative diagnosis based on colonoscopy/barium enema, followed by histology and the imaging methods, in most cases US and/or CT. Patients with postoperative stage Dukes D and after palliative surgery were excluded from the follow-up study (n = 43). The patients were seen every three months (clinical investigation, US, CT, tumor markers, FOBT) within the first two postoperative years and every half a year thereafter. 83 of the 116 patients (16%) developed a recurrent disease and 5 of them could be reoperated with curative intention. In addition to the 19 patients 14 simultaneously admitted patients with recurrence of colorectal cancer (total n = 33) were studied. The results of our study analyzing the sensitivity and specificity of colonoscopy, tumor, markers and the FOBT in the preoperative and postoperative phases as well as in the diagnosis of recurrent disease of colorectal cancer confirms the view that FOBT and tumor markers cannot replace endoscopic and imaging methods. However they support the concept, that diagnosis and follow-up of colorectal cancer should be based on a combination of clinical investigation and imaging methods (US, CT etc. and endoscopic and/or x-ray examination) with supplementation by FOBT and determination of tumor markers, mainly CEA. In the case a patient is asking for prognostic and recurrence information as early and as valid as possible we currently recommend the following procedure for the first two years after surgery: every three months the determination of tumor markers, FOBT as well as ultrasound of the upper abdomen and CT of the lower abdomen and every half year a total colonoscopy. The question of whether this program will also have a therapeutical relevance depends on several factors like the personal experience and concepts of the consulting surgeons and oncologists and also on the tasks and duties which are considered worthy by the patient for his further life if confronted with the diagnosis of recurrent colorectal cancer.
Since 1997 we have prospectively tried to assess/confirm the diagnostic value of MR-Cholangiopancreaticography (MRCP) and MR-Angiography in patients suffering from pancreatic carcinoma. Till today we have studied 116 adult patients with two 1,5 Tesla MRT scanners using a body phased-array coil: 27 patients with benign diseases of the pancreas, 58 with carcinoma of the pancreas, 15 with no disorder of the pancreatobiliary system, 14 with hepatic abnormalities and 2 with other tumors. MR examinations included routinely T1-weighted (TSE, SE), T1-weighted fat-suppressed (TSE, SE), T2 weighted fast turbo spin-echo (UTSE, Haste), T2-weighted fat-suppressed fast turbo spin-echo (SPIR), 2D-cholangiopancreaticography (images were obtained with breath-held) or 3D-cholangiopancreaticography (images were obtained in coronal and axial plane with respiratory triggering). In cases with pancreatic cancer we added MR-angiography. MR images were retrospectively compared with CT, ERCP amd sonography data. Summarizing the results confirm that MRCP is a safe and non-invasive technique for studying pancreatic and biliary diseases which yields information in many cases complemontory to ERCP and PTC. MRCP images can also be used as a guide for subsequent interventional procedures. MRCP will, therefore, allow the restriction of ERCP and PTC to more therapeutical indications and cases offering special problems. Considering staging and follow-up of pancreatic cancer, MRCP cross-sectional images and MR-angiography should be performed, allowing the visualization of the extraductal anatomy/pathology. These techniques may provide the clinicians with complementary information compared to other conventional imaging methods like US and CT. Clinicians engaged in pancreatic oncology, therefore, should have MRCP, MR-angiography and MR imaging available in addition to the conventional diagnostic tools.
Stimulated by surprising results in the first 7 patients treated with intraarterial/systemic chemotherapy with a combination of Mitomycin-C + Gemcitabine we now report on the data of 28 pancreatic cancer patients in comparison to 15 patients treated with gemcitabine alone(1000 mg/m2). Tumor response was evaluated on the basis of imaging methods, tumor markers and life quality parameters like body weight, pains and Karnofsky index etc. Tumor markers were monthly determined, imaging methods every 1-3 months. The locoregional/systemic approach included 3 week cycles with i.a. application of mitomycin-C + gemcitabine on day 1 and i.v. application of gemcitabine on days 8 and 15. The alltogether 125 cycles (mean 4 cycles per patient) resulted in 43% PR (n = 12), 1 CR (3%), 255 MR, 11% SD and 18% PD in the imaging methods and 20% CR, 60% PR, 4% MR and 12% SD in the course of the relevant tumor markers. Progression free survival amounted to a median of 7.5 (6) months defined by imaging methods (tumor markers). Second line treatments following new progress after effective locoregional approach with gemcitabine or a combination of gemcitabine + oxaliplatin did not result in a new tumor regression. However, third line therapy trials in 3 patients with high dose 5-FU or CPT 11 induced new antitumoral efficacy (survival of these tumors > 15, > 17 and > 28 months, n = 2 M1, n = 1 T3M0). About 75% of patients reported on a relevant benefit of life quality parameters. Side effects are on principle comparable to those of gemcitabine monotherapy, except for a tendency to a higher rate of pulmonary complications and 1 HUS observed. Even if not compared in a randomized study locoregional/systemic combined treatment modality seems to result in a higher rate of abjective tumor response defined by imaging methods as well as tumormarkers. Comparing tumor marker and imaging response to therapy CA 19-9 often showed a more rapid and subtle answer to therapy and an earlier new increase suggesting tumor markers as an essential part in the follow-up of these patients in order to optimize the patient's palliative treatment. Our results should stimulate the clinicians to rediscuss the chemosensitivity of exocrine pancreatic cancer and to perform prospective randomized studies focusing on combined gemcitabine approaches.
The majority of pancreatic carcinomas contain a mutation at codon 12 of the K-ras oncogene. We have analysed 87 samples from 76 patients who underwent surgery because of different pancreatic diseases to evaluate whether the detection of K-ras mutations may be helpful to discriminate between chronic inflammation and neoplastic growth. Mutation analysis was performed using a semi-nested PCR followed by a selective restriction enzyme digestion. The correlation of clinical follow ups with the results of the molecular analysis was performed from 47 patients. K-ras mutations were detected in 50% of adenocarcinomas and no point mutation was found in normal pancreatic tissue and in tumor tissue from entities other than pancreas. Otherwise, K-ras mutations were detected in tissue samples from two patients with chronic pancreatitis, and one patient was found to have an adenocarcinoma after additional clinical investigation. Further studies especially follow ups will be helpful to get a better insight into the pathogenesis of pancreatic tumors and may be useful as an early diagnostic test.
BACKGROUND: In a previous phase II trial of ifosfamide (IFO) several patients with pancreatic cancer responded to therapy (1). Trofosfamide (TROFO) is an orally taken oxazaphosphorine prodrug. Metabolic products of TROFO include ifosfamide (IFO) and cyclophosphamide (CYCLO). In clinical pilot studies with TROFO against refractory malignancies mild toxicity was reported. PATIENTS AND METHODS: Since virtually all patients with advanced pancreatic cancer are symtomatic, we designed and conducted a prospective phase II trial to evaluate the activity of single agent therapy with TROFO given orally continuously (three times 50 mg daily), and to assess the toxicity, duration of remission, and overall survival of the treated patients. RESULTS: 16 patients were enrolled onto the study. In one patient a PR has been observed; the mayor response rate was 6%. The mayor toxicity was bone marrow toxicity with granulocytopenia (WHO grade II) and anemia (WHO grade II) in virtually all patients. CONCLUSION: Single agent therapy with TROFO in patients with pancreatic cancer is safe and well tolerated; however, it shows low clinical activity.
BACKGROUND: Elevated plasma levels of tumor markers may be caused by diseases other than malignancy, i.e. kidney, liver or circulatory disturbances. These conditions are not well defined, especially since there are only sparse reports on fluctuations of tumor markers related to cardiac function. PATIENTS AND METHODS: During our routine pre- and postoperative follow-up tumor marker determinations in heart failure patients were made in order to screen for possible occult neoplasm's which may either be a contraindication or a sequela of heart transplantation. The markers CA 12-5, CEA, CA 19-9, CA 72-4, TPA, TPS and CYFRA 21-1 were determined at three month intervals, besides clinical examination and hemodynamic measurements in a total of n = 118 patients pre- and n = 74 patients post heart transplantation. RESULTS: The results were grouped according the clinical status (NYHA-stage 1-4): CA12-5 (29.4 +/- 40.63 omega 151, 174 +/- 345 and 491 +/- 633 U/ml, p < 0.001 between all groups) and TPS (64 +/- 32, 118 +/- 153, 163 +/- 311 and 181 +/- 232 U/ml, p = 0.06 between all groups) were increasingly elevated in NYHA stages 1, 2, 3 or 4 respectively. A direct correlation to right atrial pressure (r = 0.41, p < 0.0001) and pulmonary capillary wedge pressure (r = 0.27, p < 0.001) was only found for CA 12-5. After heart transplantation a normalization of elevated pre-OP levels could be found. Comparable to heart failure patients poor graft function was also associated with elevated levels of CA 12-5 (113 +/- 99 vs 21.6 +/- 31 U/ml, p < 0.0001), CA 72-4 (8.4 +/- 3 vs 3.6 +/- 4, U/ml p = 0.03) and TPS (154 +/- 133 vs 66 +/- 28 U/ml, p < 0.001). The individual time course of the markers, especially of CA 12-5, correlated nicely to clinical events and hemodynamic measurements in some patients. Another finding was that CYFRA 21-1 levels were correlated to renal function. CEA, CA 19-9 and CYFRA 21-1 serum levels were not influenced by circulatory disturbances. CONCLUSION: We concluded that the tumor markers CA 12-5 and TPS (but not CEA, CA 19-9 and CYFRA 21-1) are associated with congestion and the clinical course of heart failure and HTx patients. These "nonspecific" changes have to be considered when tumor markers are determined in cancer patients with heart failure. Whether CA 12-5 blood levels may yield additional prognostic information in the management of cardiovascular patients has to be determined in further studies.
BACKGROUND: The definite diagnosis of pancreatic tumors of unknown origin remains a clinical challenge. Imaging techniques may fail to differentiate malignant tumors from inflammation, especially in chronic pancreatitis. In a considerable number of cases, the definitive diagnosis needs laparotomy. Single tumor markers as CA 19-9 or CEA are of limited value in these cases because of their limited sensitivity and specificity. This study was performed to find out, whether a classification method based on fuzzy logic analysis of tumor marker profiles is feasible in patients with pancreatic carcinoma and benign pancreatic disease. PATIENTS AND METHODS: Tumor markers and other clinical and laboratory parameters of 74 consecutive patients, either with histologically proved pancreatic carcinoma (n = 43) or presumed benign pancreatic disease (n = 31) assessed by ultrasound, endoscopic retrograde pancreatography, or computed tomography were analysed in order to detect their diagnostic value in the multi-dimensional approach of fuzzy logic analysis. RESULTS: Given a specificity of 95%, sensitivity was considerably increased by the fuzzy logic method (83%) compared with the best single tumor marker CA 19-9 (65%). CA 19-9, CYFRA 21-1 and CA 15-3 gave the most considerable contributions to the classification system, whereas CEA, CA 125, CA 72-4, AFP, liver enzymes, lipase, amylase, bilirubin, and ferritin were of no or little value. CONCLUSIONS: Tumor marker profiles analysed with the fuzzy logic method may have an improved sensitivity compared with single standard tumor markers. The diagnostic efficacy should be proved in patients with pancreatic tumors of unknown origin.
Results of palliative chemotherapy in 104 patients suffering from exocrine pancreatic carcinomas are presented. First-line therapy included intraarterial approaches with gemcitabine + mitomycin-C and intravenous systemic treatments with gemcitabine, gemcitabine + mitomycin-C and oxaliplatin, respectively. In addition, it was the aim to improve survival by adding second- and third-line chemotherapies, mainly including high dose 5-FU/FA and irinotecan resp. alone or in combinations. Follow-up included clinical investigations, imaging methods and determination of tumor markers. Evaluation of efficacy followed the WHO guidelines. The results indicated the intraarterial locoregional treatment of exocrine pancreatic cancer with a combination of mitomycin-C + gemcitabine as a highly effective treatment modality with PR + CR of 40% measured by imaging methods and 81% analysed by tumor marker determinations. The survival analyses suggested relevant prolongation of survival in relation to the number of effective second- and/or third-line therapies (0/1/> 1) with median survival--based on the imaging data--of 7, 11 and 20 months for Mo tumors and 3, 8 and 14 months for tumor diseases with liver metastases at time of admission, respectively. Relevant preconditions for second- and/or third-line therapies of pancreatic carcinomas are given by more or less effective first-line treatment modalities of this cancer disease on the one hand and by the actual diagnostic aids allowing the beginning of first-line therapy as well as the detection of recurrence early enough to try a second- or third-line therapy before clinical/ethical aspects prevent further antitumoral treatment trials in the individual patient.
Following the concept that the actual survival of pancreatic cancer patients can only be significantly improved by sequential poly-chemotherapy (EOSPC) in order to add one or two further progression free-survival times (PFST), in addition to the potential antitumoral effects of a first- or second-line therapy we studied the therapeutic efficacy of a third- or fourth-line chemotherapy with irinotecan alone, or in combination with oxaliplatin and high dose 5-FU/FA respectively, in a pilot study in 17 patients. Follow-up was performed on the basis of clinical investigations, imaging methods and the course of tumor markers, mainly CT and CA 19-9. The overall response rate in these cases of third/fourth-line therapies was 1 PR, 4 MR, 6 SD in the imaging methods compared to 5 PR, 2 MR and 5 SD on the basis of the tumor marker courses in the serum. The median PFST amounted to 4 months. Side effects could be seen as reported in the literature. Only in 1 patient did treatment have to be stopped due to irinotecan-induced gastrointestinal symptoms. Our data might suggest that combinations are more effective than irinotecan alone. However, further studies have to demonstrate whether irinotecan alone or in combination with e.g. oxaliplatin and 5-FU/FA will be more effective. The results suggested that irinotecan alone or in combination might also be used as third- and fourth-line therapeutical trials in exocrine pancreatic cancer in order to improve the survival time of these patients based on efficacy orientated sequential poly-chemotherapy (EOSPC).
The results of palliative chemotherapy in 162 patients suffering from exocrine pancreatic cancer are presented. They are mainly discussed with respect to the possibility of improving survival of exocrine pancreatic cancer patients by an efficacy-orientated sequential polychemotherapy (EOSP). In about 40% of the patients treated between 1998 and 2001, sequential chemotherapy induced more than one effective treatment in the case that SD after a progressive prephase as well as MR, PR and CR are considered as antitumoral efficacy. Sequential polychemotherapy seems to be able to prolong the survival of these patients. The whole group of patients showed a 1-year survival of 56% and a 2-year survival of 16%. Especially in the case of metastasized tumor disease (M1), sequential polychemotherapy seems to be able to prolong survival: 45% of the metastasized tumor patients survived more than 1 year, 12% more than 2 years. The median survival for the whole group of locally advanced tumors was 15 months and the median survival for the whole group of metastasized tumors was 8 months. The results should stimulate clinicians to try palliative chemotherapy for pancreatic cancer more actively than before and to rediscuss the actual concepts of prospective therapeutical trials mainly based on analysing the effects of single agents or drug combinations on survival.
We report on 4 cancer patients with transient unspecific elevations of the serum tumor markers CA 19-9, CEA, CA 125 and CA 72-4, respectively. In one patient cholangitis due to biliary obstruction induced a significant transient increase of CA 19-9, in another patient HUS, probably as a severe complication after Mitomycin-C + Gemcitabine therapy resulted in a significant increase of serum CA 125. One patient demonstrated an extensively elevated and inexplicable serum CA 19-9 concentration (9450 u/ml) during a period of abdominal pain with continuous decrease and finally normalization within the following 5 years. Also inexplicable is an unexpected remittent increase of serum CA 72-4 in the course of chemotherapy after gastrectomy for gastric carcinoma. The presented data underline the necessity of interpreting serum courses of tumor markers only in the light of all available clinical data, imaging data and other laboratory tests in order to avoid misinterpretations.
The results of palliative chemotherapy in 55 patients suffering from exocrine pancreatic cancer are reported, following our concept of efficacy orientated sequential polychemotherapy (EOSPC). Tumor answer/regression was mainly analyzed on the basis of the serum courses of the tumor markers CA 19-9 and CEA. Up to four different treatment trials were tried in the individual patients. The results confirm previously published data: a prolongation of survival in relation to the number of effective treatments (CR/PR/MR/SD vs. PD). The median survival of the whole group of patients (n=55, including n=39 patients with distant metastasis) was 12 months. The results support our concept of EOSPC in pancreatic cancer patients in order to improve survival. Furthermore, the data should stimulate attention not only on new and potentially more effective 1st- line regimens, but also to effective 2nd- and/or 3rd-line treatments. Moreover, the results should encourage clinicians to rediscuss the actual concepts of prospective therapeutical trails mainly based on analyzing the effects of single agents or drug combinations on survival. Furthermore, a comparison of 1st-line treatments with gemcitabine as monotherapy, and in combination with mitomycin-C, confirms that the combination of gemcitabine + mitomycin-C seems to be more active than gemcitabine monotherapy and that this combination might also be of value as 2nd-line therapy after gemcitabine monotherapy.