Peripheral primitive neuroectodermal tumor: challenge for multimodal treatment.

The primitive neuroectodermal tumor (PNET) is an extremely aggressive soft tissue neoplasm that occurs in children and adolescents. We retrospectively reviewed our therapeutic experience with a multidisciplinary approach, combining surgery, chemotherapy, and radiation therapy. Treatment of PNET was carried out in compliance with the soft tissue protocol (CWS) from the German Society of Pediatric Oncology. Biopsy-proven diagnosis was followed by chemotherapy, which in all cases led to partial remission, allowing excision of the remainder of the tumor without mutilation. After excision, irradiation of the tumor site and two further sequences of chemotherapy were performed. When PNET of the paravertebral region caused symptoms of paralysis and immediate surgery was required, postoperative chemotherapy, a second-look operation, and irradiation were undertaken. Between 1986 and 1998 we treated 13 patients (median age 15 years). In five patients the PNET originated from the chest wall and in eight patients from the paravertebral and retroperitoneal region. Five patients died after 20 months on average, and the remaining eight patients are in full remission after 7, 16, 46, 55, 70, 74, 75, and 115 months, respectively. Close cooperation between surgeons and their pediatric and radiotherapy colleagues is obligatory when treating PNET. Chemotherapy as the first stage is mandatory to avoid a mutilating surgical procedure and intraoperative tumor cell dissemination.

[Ciprofloxacin levels in pleural fluid and serum during systemic administration after pneumonectomy]. / Ciprofloxacin-Spiegel im Serothorax nach Pneumonektomie bei systemischer Applikation.

Postpneumonectomy empyema represents a frequently lethal complication. It remains unsolved whether prophylactic antibiotics achieve a bactericidal concentration in the pleural cavity after pneumonectomy. 12 patients undergoing pneumonectomy received ciprofloxacin intravenously (2 x 200 micrograms/d) and orally (2 x 500 micromilligrams/d) during the first and second postoperative week, respectively. 1, 6, 9 and 14 days after the operation the ciprofloxacin concentration was measured in the pleural fluid and serum. Already after 24 hours bactericidal levels (0.56 microgram/ml) were found in the pleural fluid, rising to 1.11 micrograms/ml on day 14 under the higher oral dosage. Thus, it could be demonstrated that during the first two weeks after pneumonectomy high concentrations of an antibiotic similar to the levels in the serum can be achieved in the pleural fluid.

The efficacy of adjuvant cytostatic therapy after organ transplantation for malignancy: an experimental study with a combined transplantation/tumor model.

New data show that perioperative cytostatic therapy is beneficial in the case of liver transplantation for hepatic cancer. However, it has not been established clearly whether chemotherapy interferes with graft rejection. We therefore studied the interactions between tumor growth and graft rejection, especially with regard to chemotherapy, using a combined tumor/transplantation model. As a tumor model, we used the Novikoff hepatoma, a malignant hepatoma that was injected subcutaneously into the backs of rats. Heterotopic heart grafting served as the transplantation model. In a first step (a), we studied the effect of cytostatic therapy on tumor growth: tumor cells were injected, and in four groups epirubicin, cyclosporine, epirubicin + cyclosporine, and placebo were applied, in corresponding groups, transplantation was additionally performed. Tumor growth was measured and the resected tumors were examined by histology and immunohistology. In a second step (b), we studied the effect of chemotherapy on graft rejection: transplantation was performed and the above-mentioned drugs were applied; in corresponding groups, a solid tumor was additionally induced and resected immediately before transplantation. The results of these procedures were as follows: (a) Epirubicin decreased tumor growth and diminished the volume-increasing effect of cyclosporine significantly. After transplantation, tumor growth was similar. (b) Epirubicin prolonged graft survival significantly, and the combination with cyclosporine had an augmenting effect. In the corresponding groups, graft survival was similar. In conclusions. chemotherapy diminishes the tumor-increasing effect of cyclosporine and does not interfere negatively with graft survival. It might therefore be beneficial after transplantation for malignancy.

The prognostic significance of tumor cell detection in intraoperative pleural lavage and lung tissue cultures for patients with lung cancer.

METHODS: Three hundred forty-two patients with lung cancer and 99 patients with nonneoplastic lung diseases (control group) underwent intraoperative pleural lavage with 300 ml physiologic saline solution before (lavage I) and after resection (lavage II). RESULTS: Studies of the lavage fluid in all control patients were negative, that is, there were no false positive findings. Tumor cells were found in lavage I in 132 patients (38.6%) and also in lavage II in 99 of them. In stage I (pT1 N0, pT2 N0) lung cancer, tumor cell detection was possible in 47 patients (28.6%). The 4-year survival of patients with resected non-small-cell lung cancer was 24% (95% confidence interval, 16% to 32%) if lavage I results were positive and 52% (95% confidence interval, 45% to 59%) if lavage I results were negative (all stages, p = 0.007). For patients with stage I disease (n = 164) the 4-year survival was 35% (95% confidence interval, 18% to 52%) if lavage I results were positive (n = 47), and 69% (95% confidence interval, 60% to 78%) if lavage I results were negative (n = 117) (p = 0.037). On multivariate analysis the positive cytologic result in intraoperative pleural lavage was an additional prognostic factor for our patients. To prove how the tumor cells enter the pleural cavity, we performed tissue cultures of tumor-free parenchyma in 23 cases of lung cancer. Tumor cell detection by histology and immunohistology was possible in 16 cases (69.6%). Detection of tumor cells in pleural lavage fluid before resection proves that tumor cells have spread into the pleural cavity. CONCLUSION: The positive result in pleural lavage seems to be a prognostic predictor for patients with lung cancer.

[Intrapulmonary tumor cell dissemination and intraoperative pleural lavage as prognostic factors in bronchial carcinoma]. / Intrapulmonale Tumorzellausbreitung und intraoperative Pleuralavage als Prognosefaktoren beim Bronchialkarzinom.

319 patients with the first manifestation of lung cancer underwent intraoperative pleural lavage (lavage I = after opening the chest; lavage II = after resection of lung cancer). Tumor cells were found in lavage I in 122 patients (38.2%), in 94 of them also in lavage II. In only 9 cases we found tumor cells in lavage II cytologically. The cumulative five-year survival rate of non-small cell lung cancer in stage I (n = 154) was 22.1% if lavage was positive (lavage I and II, n = 44), and 64.3% if lavage was negative (n = 110) (p < 0.05). Additionally, we performed tissue cultures of tumor-free parenchyma in 23 cases of lung cancer. In 16 cases (69.6%) we detected tumor cells by histology and immunhistology. Intraoperative pleural lavage should be done when assessing the final tumor stage. A positive result should be added to the pTNM-classification of lung cancer.

[Value of systematic lymphadenectomy in stomach carcinoma]. / Die Bedeutung der systematischen Lymphadenektomie beim Magenkarzinom.

In a retrospective study of 157 patients undergoing a curative resection of a gastric carcinoma between 1982 and 1992 the correlation of the lymph node status and histomorphologic parameters of the gastric cancer and the significance of the systematic lymphadenectomy were analysed. The patients were divided into two historical groups (exclusively D1- and systematic D1-/D2-lymphadenectomy). Among the histomorphological parameters only the depth of infiltration (pT) revealed a high correlation with the extent of metastatic lymph node involvement. Tumor form, Laurén-classification and tumor localisation only showed a marginal influence on the nodal status. The overall 5-year survival rate was not significantly changed by the systematic lymphadenectomy, only the subgroup of the UICC-stadium II demonstrated a small benefit. The extended systematic lymph node dissection did not rise the complication rate but lowered the rate of local recurrences. In conclusion, the indication for a systematic lymphadenectomy cannot be deducted from the constellation of different histomorphological parameters, but the feasibility of a systematic lymphadenectomy results from the improvement of staging and survival rate at least for the UICC-II-stadium and the reduction of local recurrences.

[Implantation metastases following laparoscopic cholecystectomy in gallbladder carcinoma]. / Implantationsmetastasen nach laparoskopischer Cholezystektomie bei Gallenblasenkarzinom.

HISTORY AND CLINICAL FINDINGS: A 66-year-old woman was known to have had cholecystolithiasis for at least 4 years. Laparoscopic cholecystectomy was performed at another hospital where histological examination surprisingly revealed middle-grade differentiated carcinoma of the gall-bladder (pT2, G2). A nodular metastasis of the gall-bladder carcinoma was noted on the abdominal wall 3 months later and excised. Lymph-vessel carcinomatosis was already present. The patient again noticed a tumour in the right mid-abdomen and a further tumour was palpated in the epigastrium 5 months after the operation. INVESTIGATIONS: Laboratory and tumour-marker (CEA, CA 19-9) tests were unremarkable, while sonography and computed tomography were highly suspicious for abdominal wall metastases in the epigastrium and right mid-abdomen. TREATMENT AND COURSE: Both metastases were excised. Laparotomy revealed tumour recurrence in the old gall-bladder bed, as well as extensive peritoneal carcinoma. Two months after the operation she developed jaundice, caused by tumour compression of the choledochal duct. An expanding stent was inserted into the stenosed section of the duct. The patient died 13 months after the first operation from the underlying malignancy with multiple liver metastases and malignant ascites. CONCLUSIONS: Indications for minimally invasive surgery in malignant tumour should be narrowly defined. Because tumour seeding is possible after laparoscopic cholecystectomy with incidentally found carcinoma extensive re-excision should be performed.

[Intrapulmonary tumor cell spread and intraoperative pleural lavage as prognostic factors in bronchial carcinoma?]. / Intrapulmonale Tumorzellausbreitung und intraoperative Pleuralavage als Prognosefaktoren beim Bronchialkarzinom?

Tumor cell detection in lavage fluids might be a prognostic factor in solid tumors. Therefore, 342 patients with the first manifestation of lung cancer underwent intraoperative pleural lavage (lavage I = after opening the chest; lavage II = after resection of lung cancer). Tumor cells were found in lavage I in 132 patients (38.6%), in 99 of them also in lavage II. We found tumor cells in only nine cases in lavage II cytologically. The cumulative 5 year survival rate of non-small cell lung cancer in stage I (n = 164) was 25.9% if lavage was positive (lavages I and II, n = 47), and 69.2% if lavage was negative (n = 117) (p < 0.05). Additionally, we performed tissue cultures of tumor-free parenchyma in 23 cases of lung cancer. In 16 cases (69.6%), we detected tumor cells by histology and immunohistology. Cytologic tumor cell detection in intraoperative pleural lavage in lung cancer seems to be an additional prognostic factor and should be done when assessing the final tumor stage. A positive result should be added to the pTNM classification.

Interactions between malignant tumor growth and allogeneic graft rejection in an experimental rat model.

We describe a combined tumor and simultaneous transplant model in rats in tended to investigate interactions between tumor growth and graft rejection. To study the influence of tumor growth on graft rejection. Novikoff hepatoma cells were injected subcutaneously into the back of Lewis rats. Eight days later, the grown solid tumor was resected, and allogeneic heart transplantation was performed. Four groups were formed, receiving 5-fluorouracil (5-FU), cyclosporin A (CsA), 5-FU + CsA, and placebo, respectively. In the corresponding groups, tumor injection was omitted. Graft survival was significantly prolonged when CsA was given 5-FU did not abrogate or augment CsA efficiency nor influence graft survival when given alone. In the corresponding control groups, graft survival was similar, thus excluding an immunomodulating effect of the prior tumor growth on graft survival. To study the reverse interaction of allogeneic graft on tumor growth, heart grafting and tumor cell injection were performed on the same day. In different groups, 5-FU, CsA, 5-FU + CsA, and placebo was given. For the control, no transplantation was carried out. The tumor was resected on the 8th postoperative day and examined by immunohistology. A slight decrease of tumor growth by 5-FU, but a marked increase by CsA were found, whereas the graft alone showed no immunomodulation.

[Effect of perioperative donor blood transfusion on prognosis of bronchial cancer]. / Der Einfluss der perioperativen Fremdblutgabe auf die Prognose des Bronchialkarzinoms.

Immunological research and experimental animal studies have shown that allogeneic blood has an immunosuppressive effect. Several clinical investigations have demonstrated the negative influence of blood transfusions on the prognosis after curative resection of colorectal carcinoma. However, there are only a few studies about the influence after complete removal of lung cancer, and the results are contradictory. In our retrospective study we analyzed the follow-up results of 224 patients (192 men, 32 women; average age 57 years) on whom we had performed a curative resection of their bronchogenic carcinoma. A total of 119 patients had received nonspecific random blood transfusions. The survival rate for patients with blood transfusions was significantly worse in comparison to the non-transfused group 2 years after the operation (74% vs 59%, P = 0.019); after 5 years, however, no difference could be seen (43% vs 43%). Even when we subdivided our patients according to tumor cell type, tumor stage, differentiation and method of resection, the negative influence of transfused blood was confirmed for the 2-year survival rate, but again had disappeared 5 years after the operation.

Synergy between subtherapeutic doses of cyclosporine and immunobiological manipulations in rat heart graft recipients.

Cyclosporine in combination with other chemical or biological immunosuppressive modalities has been useful in clinical and experimental organ transplantation. In these studies, the efficacy of adjunctive subtherapeutic doses of CsA given to immunologically enhanced heart graft recipients or to animals treated with an anti-IL-2 receptor monoclonal antibody (ART18) are described. Individually, the treatment entities are only partially effective. In rats undergoing active and passive enhancement alone, heart allograft survival was increased to 25 +/- 12 days in two-thirds, indefinitely in one-third. After ART18 treatment, grafts survive 21 +/- 1 days. Grafts are accepted permanently in animals receiving full-dose CsA (15 mg/kg X 7), but are rejected acutely (c. 7 days) when subtherapeutic doses (1.5 mg/kg X 7) are used. However, when subtherapeutic doses of CsA are given in combination with immunological enhancement or with interleukin-2-receptor-targeted therapy, graft survival increases dramatically, with permanent or markedly prolonged engraftment occurring in all instances. In the early phases of host unresponsiveness, both enhancement and IL-2R-targeted therapy, graft survival increases dramatically, with permanent or markedly prolonged engraftment occurring in all instances. In the early phases of host unresponsiveness, both enhancement and IL-2R-targeted therapy spare selectively T cells with suppressor activity in vivo; in enhanced animals, the W3/25+ subset is responsible for prolonged graft survival, the OX8+ fraction is responsible in ART18-treated animals and in CsA-treated animals. Both subpopulations show suppressor activity in the later stages of combination treatment. IL-3 production is increased significantly in these states of unresponsiveness, an observation also noted during maintenance CsA treatment; this seems to correlate with suppressor activity. Immunoperoxidase studies of the graft infiltrates emphasize the synergistic effects of combination treatments. Thus, subtherapeutic doses of CsA plus biologic host manipulations produce greatly increased graft survival by affecting selectively different host immune mechanisms.

Synergy between subtherapeutic doses of cyclosporine and immunologic enhancement in rat recipients of cardiac allografts.

We have analyzed the adjunctive effect of subtherapeutic doses of cyclosporine (CsA, 1.5 mg/kg/day x 7 or 14 days) on cardiac allograft survival in actively and passively enhanced rats. This CsA dose, one tenth of the effective dose, when administered after, but not before, transplantation into enhanced hosts produced permanent graft acceptance; cardiac allografts survive c. 25 days in recipients enhanced only and 1 week in untreated animals. Adoptive transfer of spleen T cells of OX8+ or W3/25+ phenotype from long-term (greater than 200 days) graft recipients prolonged donor-specific test graft survival in naive rats (c. 16 days and c. 14 days, respectively, P less than 0.001) and delayed rejection in reconstituted B rats from 7 days to 21-23 days (P less than 0.001). Indeed, both T subsets were separately equally potent and with no overlap responsible for the suppressor activity. The phenotypic profile of the immune cells in the maintenance phase of enhanced or enhanced + CsA-treated recipients was comparable to naive or isografted controls as demonstrated by flow cytometry and immunohistologic studies. Furthermore, the activation status of the graft infiltrate in long-term survivors was similar regardless of the initial immunosuppressive protocol. CsA contributed selectively to the enhancing regimen in the induction phase of unresponsiveness, diminishing the cellularity of graft infiltrate and preventing intragraft T cell activation. These studies stress synergy between subtherapeutic doses of CsA and immunologic active/passive enhancement, 2 immunosuppressive modalities that spare T cells with suppressor capabilities but differ in the inhibition of T helper cell activation.