Therapeutic strategy of papillary cystic and solid neoplasm (PCSN): a rare non-endocrine tumor of the pancreas in children.

Papillary-cystic and solid neoplasm (PCSN) are rare tumors. Two personal observations and a review of the literature are presented with a total of 44 pediatric patients in addition to a total of 67 published cases in the review of Cohen (Pediatr. Surg. Int. 6 (1991) 128) and Snadjauf (Eur. J. Pediatr. Surg. 9 (1999) 416). Overall, PCSN shows a clear predominance in females and only occasionally occurs in males. Typically they grow to a large tumor mass with minimal symptoms. Their histologic and immunocytologic characteristics cause diagnostic difficulties, especially on frozen sections of small biopsies. The tumors are assumed to origin from pluripotent stem cells and present as tumors of low malignancy with a favorable prognosis. Nevertheless 10 children have been reported to develop metastases, 5 have demonstrated an invasive growth pattern and 4 local recurrence. But only two of the 111 pediatric cases have died from their tumor burden. Treatment of choice is a complete surgical resection, which is true for the primary tumor and for metastases as well as local recurrences. In our 2 patients one had spleen-conserving left pancreatic resection and one mesopancreatectomy with roux-en-y-reconstruction leading to long-term cure. Adjuvant therapy in curative resected patients is unnecessary and does not appear to improve prognosis.

Autoradiographic study on the effect of hyperthermia (42.5 degrees C) on the proliferation kinetics of solid tumors in children.

Supranormal temperatures between 40 and 43 degrees C are not necessarily lethal to tumor cells, but lead to characteristic changes of the cell cycle. The parameters of the proliferation kinetics were studied in 35 solid tumors of children at a temperature of 42.5 degrees C with an autoradiographic in vitro method, in comparison to normothermia: 9 Wilms' tumors, 10 neuroblastomas, 8 osteogenic and soft tissue sarcomas, 6 non-Hodgkin-lymphomas, and 3 other tumors. 28 tumors showed significant prolongation of DNA synthesis times by an average factor of 1.27 (1.10--3.12). Mitosis times undergo an average prolongation by the factor 2.75 (1.07--8.87). Together with significant decrease of the 3H-thymidine labeling index the prolongation of the cell cycle time amounts to an average of 2.67 (1.05--8.30). The cause of the changes of the cell cycle are discussed. Probably, the heat sensitivity of tumors is correlated with the proliferation rate and with the degree of histological differentiation; but this cannot be confirmed statistically due to the small number of cases. 2 cases responded with a decrease of the duration of the cell cycle; in one case this was probably due to an exogenic thermotolerance. The changes of the cell cycle are of a particular importance for the therapeutic combination with radio- or chemotherapy. These relations are discussed.

The effect of hyperthermia alone or in combination with actinomycin D on the RNA metabolism of solid tumors in children.

The incorporation of 3H-uridine into the RNA was studied under normothermia 37 degrees C/120 min, hyperthermia 42.5 degrees/120 min, and both in combination with Actinomycin D by an autoradiographic in vitro method in 19 solid tumors of children: 6 Wilms' tumors, 5 neuroblastomas, 4 osteogenic sarcomas, and 4 different tumors. Hyperthermia invariably reduces the 3H-uridine incorporation into RNA by 11.7--86.4%, with an average of 47.5%. Actinomycin D consistently inhibits the 3H-uridine incorporation between 27.7 and 99.8%, with the average inhibition of 62.0% being far greater than that recorded for hyperthermia. The highest degree of 3H-uridine incorporation inhibition is obtained using hyperthermia in combination with Actinomycin D. The inhibition varies from 45.5--99.8%, with an average of 81.4%. In spite of the general regularity, the effect of hyperthermia and Actinomycin D are characterized by individual patterns. Obviously, they are dependent on proliferative activity rather than upon the particular type of tumor. The use of supranormal temperatures for the treatment of malignant tumors in man, also in combination with radiation or cytostatic drugs, is a possible and promising method of therapy.

The sensitivity testing of Wilms' tumors to cytostatic agents with an autoradiographic in vitro short-term test.

Sensitivity of 15 Wilm's tumors in children was tested towards cytostatic agents in vitro by means of an autoradiographic short-term test. Sensitivity was measured as a magnitude of the inhibition of 3H-thymidine, resp. 3H-uridine incorporation. The test was performed with Adriamycin, Actinomycin D. Daunomycin, Bleomycin, Cyclophosphamide, Ifosfamide, Trenimon, and Arabinosylcytosine. None of the tumors is resistant to all substances, they are responsive against 2 or more drugs. The most effective drugs tested are Adriamycin, Actinomycin D and Cyclophosphamide. The tumors show a marked individual sensitivity pattern. This behavior is explained mainly by the usually high proliferative activity of Wilms' tumors. The possibilities and limits of long-term and short-term methods for sensitivity testing are discussed critically. For the evaluation of the results of in vitro testing and in vivo effectiveness the close correlation should be considered between the type of cytostatic agent and proliferation kinetics of the tumor, cytostatic agent and effect on tumor metabolism as well as the effect of the cytostatics and the nucleic acid precursors used for the short-term test. Despite the methodological limitations preclinical testing should be preferred to unselected chemotherapy.

Pancreatoblastoma in children. Case report and review of the literature.

Pancreatolblastomas are rare embryonal malignancies in childhood. We report a 3-year-old girl with a tumor of the head of pancreas. Staging by bone scintigraphy and CT scans of abdomen and chest did not show evidence of metastatic disease. Tumor markers showed elevated levels of alpha-1 fetoprotein (64 ng/ml; normal 0-10 ng/ml) and lactate dehydrogenase (423 U/l; normal range below 300 U/l). The tumor was macroscopically completely removed by local resection. Postoperative tumor grading was pT1, NO, MO. The child recovered very soon after surgery without severe complications. Tumor markers dropped to normal values, indicating complete remission (follow-up time 12 months). According to the biological growth characteristics of pancreatoblastomas and to the literature, localized and non-metastatic tumors should be completely resected without radical pancreatoduodenectomy and without adjuvant chemotherapy. This is the most conservative therapy with a good prognosis. However, metastatic disease, primarily inoperable conditions or local relapses are indications for chemotherapy combined with radiotherapy and followed by resection of the tumor. At present, the prognosis of such cases is rather poor.

Neurogenic appendicopathy in children.

BACKGROUND: In a prospective multicenter study, we could show that neurogenic appendicopathy is a histological entity. This study compares the general and the pediatric population with respect to clinical presentation and incidence of neurogenic appendicopathy (NA). METHODS: Included were patients that underwent appendectomy for suspected appendicitis, excluded were patients younger than 6 years and patients with missing data. Neurogenic appendicopathy was diagnosed by S-100 immunochemistry and/or haematoxylineosin (H.E.) staining. Two age groups (< or = 14 y and > 14 y) were compared with respect to the frequency of NA. RESULTS: In only four cases out of 84 children (4.8%) did we find neurogenic appendicopathy compared to 48 patients (24.2 %) out of 198 adolescents and adults. In the subgroup with negative appendectomy, the frequency of NA was 16.7% (< or = 14 years) and 56.6% (> 14 years). A clinical differentiation between neurogenic appendicopathy and acute appendicitis was not possible because of the small sample size. CONCLUSION: Neurogenic appendicopathy is a very rare histopathological entity in children. History and clinical examination do not make it possible for us to differentiate preoperatively between acute appendicitis and neurogenic appendicopathy.

[Effect by proliferation kinetics of malignant tumors of children of hyperthermia]. / Beeinflussung der Proliferationskinetik maligner Tumoren des Kindesalters durch Hyperthermie.

Embryonal tumors (21 Wilms' tumors, 11 neuroblastomas, 9 rhabdomyosarcomas) and 16 sarcomas of the skeleton of childhood were studied with an autoradiographic in vitro method according to the responsibility to hyperthermia 42.5 degrees C/120 min, to Cyclophosphamide, to Doxorubicin, and to Actinomycin D, and also to the combined application of hyperthermia and cytostatic drugs. Hyperthermia alone reduced the median 3H-thymidine, respect. 3H-uridine incorporation between 38.1 and 56.8%, respect, 45.9 and 63.9%. Hyperthermia inhibited the RNA synthesis stronger than the DNA synthesis. The combined application of hyperthermia and the different cytostatic agents increased the inhibition of incorporation of the labeled precursors extraordinarily (by Cyclophosphamide to 81.6-90.8%, by Doxorubicin to 60.8-80.0, by Actinomycin D to 79.4-93.2%). In case of the inhibition of 3H-thymidine or 3H-uridine incorporation lower than 40% (resistance), in each case the combination of hyperthermia and cytostatic drug overcomes the resistance. The consequences of hyperthermia sensitivity testing of solid tumors of human beings are discussed.

[Testing of solid tumors in childhood for sensitivity against cytostatic agents using an autoradiographic in vitro method (short-term method) (author's transl)]. / Die Zytostatikum-Sensibilitätstestung solider Tumoren des Kindesalters mit einer autoradiographischen in vitro-Methode (Kurzzeittest).

The sensitivity of 37 solid tumours of children was tested in vitro towards cytostatic agents by means of an autoradiographic short-term method. Sensitivity was measured as the magnitude of inhibition of 3 H-thymidine incorporation. The test was performed with the cytotoxic agents Cyclophosphamide, Trenimon, Bleomycin, Adriamycin, Daunomycin, Actinomycin D, and Cytosin-Arabinosid in 9 Wilms' tumours, 9 neuroblastomas, 7 non-Hodgkin-lymphomas, 5 osteogenic sarcomas, 3 soft tissue sarcomas, and 4 special tumours. None of the tumours is resistant to all cytotoxic substances. The tumours show a marked individual sensitivity pattern, and, with few exceptions, they are sensitive against 2 or more cytostatics. This behaviour is explained mainly by the usually high proliferative activity of dysontogenetic tumours, malignant lymphomas and various sarcomas. The possibilities and limits of the short-term methods for sensitivity-testing are discussed critically and in detail. For the evaluation of the results of in vitro testing and of in vivo effectiveness the close coreelations are not always taken into consideration between the type of cytostatic agent and effect on tumour metabolism, cytostatic agent and proliferation kinetics of the tumour as well as the effect of the cytostatics and the nucleic acid precursor used for the test. Despite the methodological limitations preclinical testing should be preferred in comparison with unselected chemotherapy.

The kinetics of cell proliferation in neuroblastomas.

The proliferation kinetics of 11histologically undifferentiated neuroblastomas were studied with an autoradiographic in vitro method (labelling with 3H-thymidine and double labelling with 3H- and 14C-thymidine). The cytokinetic parameters revealed a marked individual pattern: LI between 3.0 and 27.8%, Ts 7.2 to 17.8 hr, Tc 13.1 to 266.3 hr, Tm 0.6 to 5.1 hr, T(G1 + G2) 4.3 to 247.6 hr. The potential tumour doubling time (without cell loss) ranges from 20.4 to 415.4 hr. The growth fraction is between 0.48 and 0.58. Cytokinetic investigations of human tumours are extraordinarily important. They cannot only characterize the growth behaviour of malignant tumours, but also provide the basis for an individual therapy. The close correlation between proliferation kinetics and tumour therapy are discussed. These relations may also be summarized in a "cytokinetic therapy index", which allows the general prediction of chemosensitivity. This index is in the field of good or sufficient sensitivity in 9 neuroblastomas; in 2 cases the response to cytostatic agents is questionable from the view-point of cytokinetics.

Comparative autoradiographic in vitro study of the incorporation of 3H-thymidine and 3H-uridine into the DNA and RNA of solid tumours in children.

3H-thymidine and 3H-uridine labelling indices (LIth and LIur) were determined simultaneously using an autoradiographic method in 19 solid tumours: 6 Wilms' tumours, 5 neuroblastomas, 4 osteogenic sarcomas, and 4 various tumours. At a LIth of 2.7 to 47.0% (average 22.3%) all LIur were significantly higher with values of 11.6 to 76.3% (average 47.4%). The difference between both indices varies by the factor 1.26 to 7.45 (average 2.83). The magnitude of 3H-uridine incorporation into the RNA is correlated to the proliferation rate as well as that of 3H-thymidine incorporation into the DNA. Rapidly growing tumours show high 3H-thymidine and -uridine labelling indices with a decrease from Wilms' tumours to osteogenic sarcomas and neuroblastomas. 3H-thymidine and -uridine incorporation into nucleic acids are discussed with reference to the cell kinetic system of a solid tumour and the course of the cell cycle. Perhaps, the 3H-uridine labelling index in the autoradiograms represents the growth fraction of a tumour. The significance of the relation of DNA to RNA synthesis for the testing of tumour sensitivity towards cytostatic agents in the short-term test is discussed.

[Mesoblastic nephroma--a malignant tumor with low grade of malignancy]. / Das mesoblastische Nephrom--ein bösartiger Tumor mit niedrigem Malignitätsgrad.

The mesodermally differentiated and only in newborns and young infants occurring mesoblastic nephroma is regarded as benign. Recidivations with malignant course, inclination to infiltration and richness in mitosis make arise doubts about the benignity despite good prognosis. The results of a proliferation-kinetic examination received by an autoradiographic in vitro method of a mesoblastic nephroma which was observed in a 20-day-old infant are characteristic for a malignant tumour of low degree of malignity: 3H-thymidine marking index 5.8%, DNA synthesis time 18.2 hours, mean generation time 141.1 hours (= 5.9 days). Growth fraction 0.28 and potential doubling time of the tumour 16.4 days. These data decisively deviate from those of the Wilms-tumours, which are cell-kinetically characterized as extraordinarily quickly growing, highly malignant tumours. The position of the mesoblastic nephroma in the system of the dysontogenetic renal tumours is briefly discussed. The ureteronephrectomy performed in time is the only necessary therapeutic measure, since also the mesoblastic nephroma follows the general rule of dysontogenetic tumours that the prognosis is the better the younger the infant is.

[Morphological examinations of congenital obstructions of the uretero-pelvic junction in children (author's transl)]. / Morphologische Untersuchungen kongenitaler Ureterabgangsstenosen bei Kindern.

Congenital obstructions of the uretero-pelvic junction of the urinary tract have severe sequelae: urine retention, hydronephrosis, and infections, leading to renal insufficiency without adequate therapy. As the operative results are not always optimal, we studied the morphology of 56 operative specimens and analyzed the structural changes. We found the following conditions causing stenosis of the proximal ureter: 47 localized hypoplasia of the proximal segments of the ureter, systematic hypoplasia in 4 cases, and hypertrophy of the total upper urinary tract in 5 cases. The intrapelvic increase of pressure and the necessary additional work cause characteristic changes of the renal pelvis in the form of hypertrophy of the muscularis and the tunica propria, fibrous destruction of the wall, and secondary formation of valves, which eventually enhance the stenotic effect of the proximal ureter. In the kidneys caliectasis, reduction and hypoplasia of the renal medulla with minor reduction of the renal cortex may be observed. Finally, infections complicate the clinical course. The choice of the surgical procedure should be determined by type and progression of the structural changes and not by personal opinions.

[The morphology of small bowel in small bowel atresia and stenosis]. / Zur Morphologie des Darmes bei Dünndarmatresie und -stenose.

The morphologic analysis of 24 operation specimens of small bowel atresia and stenosis reveals: 1. The classification in the 4 common types of atresia is without importance for the operative management in the newborn. 2. Widely important are systemic structural changes of the atretic, preatretic, and the oral small bowel, the associated intraabdominal malformations, and the mucoviscidosis. The morphological damages at the small bowel in atresia are shown in detail. In some cases the results of the histological examination elucidate vascular alterations caused by small bowel obstruction, The severe destructing pre-atretic small bowel should be resected.

[The role of cell proliferation kinetics and cytostatica - test for sensitivity of neuroblastomas, recurrent tumours and tumour metastases (author's transl)]. / Die Bedeutung von Zellkinetik und Zytostatika - Sensibilitäts-testung von Neuroblastomen, Rezidivtumoren und Tumor-metastasen.

Using auto-radiographic techniques in vitro studies performed to analyse the growth rate in 13 cases of neuroblastoma, 6 recurrent tumours (assorted) and 7 metastatic tumours. The cell kinetic parameters using 3H thymidine markers, DNS synthesis, mitotic rate and mean cycle rate were investigated. The growth rate can only be calculated approximately. The results show that neuroblastomas grow incredibly fast. The cell-cycle period varies between 13.1 and 266.3 hours and averages 71 hours. Recurrent tumours have a tendency to have the same growth rate as the primary tumour. Primary metastases of Wilm's tumours and osteogenic sarcomas proliferate rapidly with a cell-cycle of 13.0- 87.0 hours (average 37.7 hours). All tumours have a distinctly individual proliferation pattern. Cell division and growth rate of malignant tumours are important in relation to radiotherapy and the use of cytotoxic drugs. These factors are expressed as a "cell-kinetic therapeutic index", which helps to predict the effectiveness of cytotoxic drugs and radiotherapy. Two cases of neuroblastoma were classified as resistant. Most tumours excluding the fibrosarcomas react well against two cytotoxic reagents. The cell-kinetic pattern and the sensitivity results are used in determining the treatment of recurrences and metastases. The relationship of these investigations in clinical practice is discussed.

Autoradiographic in vitro study of the cell kinetics of osteogenic sarcomas and Ewing's sarcomas in children.

Proliferation kinetic parameters of 9 osteogenic sarcomas (6 primary tumours, 3 lung metastases) and 3 Ewing's sarcomas were determined using an autoradiographic in vitro method (single and double labelling with 3H- and 14C-thymidine, and 3H-uridine). Osteogenic sarcomas and Ewing's sarcomas, respectively, showed clearly individual pattern of proliferation. The following values were obtained: The average 3H-thymidine labelling indices of 13.8/8.7%, the DNA synthesis times of 12.2/14.4 hours, mitosis times of 1.1/1.9 hours, and mean cell cycle times of 58.0/78.2 hours. The potential tumour doubling times determined with the inclusion of the growth fraction averaged 4.8/5.0 days. Using 3H-uridine labelling of tumours, autoradiography allowed the determination of the growth fraction fair accuracy. It is between 0.26 and 0.71 for osteogenic sarcomas, the average being 0.49. In vitro results were compared with the volume doubling times of metastases of osteogenic and Ewing's sarcomas, reported in the literature which had been determined from series of lung radiographs. The importance of cell kinetic studies of human tumours therapy is demonstrated by a "cell kinetic therapy index".

[Cell proliferation kinetics of solid tumors in childhood]. / Die Proliferationskinetik solider Tumoren des Kindesalters.

With the aim to develop an improved individual therapy of tumor-affected children, tumor particles were in vitro incubated with radioactively labeled precursors in order to determine the parameters of cell proliferation kinetics. The growth rate of the tumors was derived from the 3H-uridine labelling index. A "cell kinetic therapy index" is calculated from the temporal ratio of the cell cycle phases S, G2, and M, which are sensitive to cytostatic compounds and radiation, and of the mean duration of the cell cycle. When the cell kinetic therapy index (ZTI) is below 0.2 chemotherapy is scarcely promising whereas it is promising at 0.5 and above. The experimental data of Wilms tumors, osteogenic sarcomas and rapidly growing neuroblastomas are in good agreement with the clinical rate of tumor remission.

[Implantable catheter systems]. / Implantierbare Kathetersysteme.

Central venous access devices represent a definitive improvement in childhood cancer therapy. The silicone elastomer catheters offer a both save and easy access, low related morbidity and acceptance by patient. Tunnelled right atrial catheter (Broviac, Hickman-Crawford or Quinton) for long-term use are firstline choice for venous access. Although ports reduce the number of complications and manipulations associated with percutaneous catheters, they are not devoid of problems. Related complications are catheter infection and occlusion or damage. The different techniques of venous vascular access and management of complications are reported.

The effect of hyperthermia 42.5 degrees C on the incorporation of 3H-thymidine into the DNA of solid tumours in childhood.

Supranormal temperatures inhibit selectively the growth of malignant cells more than that of normal cells. The autoradiographic determination of the 3H-thymidine-labelling-index (LI) in vitro is a suitable method for the examination of thermosensitivity of individual human tumours. 44 solid tumours of children (Wilms' tumours, neuroblastomas, osteogenic sarcomas, non-Hodgkin-Lymphomas and other tumours) were studied by the temperatures 37.5 and 42.5 degrees C/120 min, with this method. 90% of the histologically undifferentiated tumours showed a highly significant inhibition of the 3H-thymidine incorporation between 28.6 and 79.9% with an average of 51.1%. In 4 histologically mature tumours (carcinoma of the adrenal cortex, malignant hepatoblastoma, fibrosarcoma, hamartoblastoma) no significant decrease of the LI was present. The inhibition of incorporation with hyperthermia cannot be correlated with the primary magnitude of the LI with normothermia. In 1 neuroblastoma a 75% rise of the LI was found possibly due to exogenic caused thermotolerance. The individuality of the reaction towards heat may contribute to the biological characterization of tumours.

[Simultaneous occurrence of Wilm's tumor and multiple lung hamartomas in a 15-year-old girl]. / Simultanes Vorkommen von Wilms-Tumor und multiplen Lungenhamartomen bei einem 15jährigen Mädchen.

The observation of multiple adenofibroleiomyomatous hamartomas of the lung in a 15-year-old girl 7 years after treatment of a Wilms' tumour caused diagnostic difficulties that are discussed. The diagnosis was finally established by thoracotomy and tumour resection. The simultaneous occurrence of Wilms' tumours and benign or malignant tumours points to genetic factors in the development of both tumours.

[Therapy of testicular tumors in childhood]. / Die Therapie von Hodentumoren im Kindesalter.

Between 1954 and 1984 41 primary testicular tumours were treated in 40 children at the age of 0 to 9 years as well as 9 secondary testicular tumours in malignant systemic diseases or metastases. The histological reclassification of the number of cases revealed 15 yolk-sac-tumours, 10 differentiated teratomas of immature subtype, 1 intermediary malignant teratoma, 3 undifferentiated malignant teratomas, 2 Sertoli-cell-tumours (1 double-sided) and 5 rhabdomyosarcomas. 2 children each with undifferentiated malignant teratomas and rhabdomyosarcomas died, all before 1970. 5 children with yolk-sac-tumours and 2 with rhabdomyosarcomas who since 1974 have been treated with Ablatio testis and combination chemotherapy live without tumour. Histological classification and division into stages are proved and form the basis of a therapy conception which in all testicular tumours apart from the Ablatio testis contains the chemotherapy of different intensity (HTK-84), taking into consideration form of tumour, stage and age of the children. The retroperitoneal lymphadenectomy is recommended only in the proof of metastases.