Transient response to alpha-interferon in juvenile chronic myelomonocytic leukemia.
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Initial combination drug regimens containing Cisplatin in patients with stage III and IV head and neck cancer produce a high percentage of clinical response. We initiated the current trial to assess the role of multimodality treatment (CT plus RT) versus CT alone in eliciting tumour response rates, and the duration of tumour free survival. Patients were randomised to CT followed by RT (arm A: 36 patients) or CT alone (arm B: 44 patients). Of 96 patients entered into this study 80 are evaluable at the time of analysis. There were 13 women and 67 men with a median age of 52 years and a median performance status of 90%. All of them presented measurable stage T4N0-3M0-1 or T3N2-3M0-1 carcinomas. The chemotherapy consisted of Cisplatinum, Bleomycin and Methotrexate and was given in 2 cycles over 35 days. Local radiotherapy with 6,000 rad followed. In arm B, 3 cycles of chemotherapy were given without radiotherapy. The overall tumour responses after CT were 75% in arm B, and 70% in arm A. After RT the tumour response fell to 59%. Median tumour remission was 4 months and median survival 11 months. Toxic effects were mild mainly consisting of alopecia, nausea and vomiting. Myelotoxicity was moderate, but significant renal or ototoxic side effects did not occur. 10 cases of Bleomycin related pulmonary fibrosis were found. Our main findings show that patients receiving 2 cycles of CT do not have a statistically shorter survival compared to those who were treated by CT plus RT.
Inoperable cases of advanced squamous cell carcinomas in the head and neck area which have a very poor prognosis are often treated by a combined radio- and chemotherapy. Tumor remissions up to 70% are induced by both radiotherapy and chemotherapy alone; an increase of the survival time is not reported. The present randomized study investigates the efficacy of two therapy schemes, i.e. chemotherapy alone and chemotherapy combined with irradiation. Tumor remissions of 75% were achieved in 80 evaluable patients, the median remission period was four months and the median survival period eleven months. The survival curves do not show any dependence of the survial time on the size of tumor or metastases. Only responders had a significantly longer survival time than non-responders.
A constitutional interstitial deletion on the short arm of chromosome #11 and an inversion of the heterochromatin of chromosome #9 were detected in a 1.5-year-old boy with Wiedemann-Beckwith syndrome (WBS) and hepatoblastoma. Of 37 malignant and nine benign neoplasms reported in approximately 250 cases with complete and incomplete forms of WBS, this is the fourth patient with hepatoblastoma. To date, 28 cases of WBS have been cytogenetically investigated with banding techniques. Constitutional anomalies have been found in only nine cases: Various anomalies resulting in a common triplication of the 11p15 region in six cases, reciprocal translocations t(11;22) and t(X;1) and an inversion of chromosome #2 in the three remaining cases. Triplication 11p15 was only present in one of four cases with a tumor. The breakpoints of the unique del(11)(p11.1p11.2) present in our case are proximal to those of del(11p13-11p14) and dup(11p15) observed thus far in both the aniridia-Wilms' tumor association and in WBS. Inversion of chromosome #9--one of the heterochromatin variants associated with elevated chromosomal instability, increased congenital abnormalities, and cancer proneness--may have been causally connected with a genetic imbalance resulting in the de novo deletion of 11p11. Therefore, we suggest that in these high-risk groups, C-banding studies should be performed together with high resolution chromosome analysis in order to also reveal the incidence and significance of C-band variants in individuals with such cancer prone syndromes.
We report the case history of a 6 1/2-month-old girl with a hemophagocytic syndrome, pancytopenia, and excessive hepatosplenomegaly. Some extraordinary histological features present in this case--restricted organ involvement, excessive hemosiderosis, and fibrosis of the spleen--further contributed to the well-known problem of distinguishing between infection-associated hemophagocytic syndrome and familial hemophagocytic lymphohistiocytosis.
During the period from 1979 until 1984 55 children were registered: 4 in Evan-stage I, 13 in stage II, 16 in stage III, 18 in stage IV and 4 in stage IV-S. 39 of these 55 patients have been followed for a minimum of two years. The current two year survival rate is 10/10 in stages I and II, 6/13 in stage III, 3/14 in stage IV and 2/2 in stage IV-S. These results demonstrate but a slight improvement in patients with stage II since the last Austrian statistic 1974. Despite modern chemotherapy the chance for survival of children with stage III or IV neuroblastoma is poor and better treatment modalities should be searched for.
This article describes the treatment of two patients with severe aplastic anaemia (SAA) by means of high-dose methylprednisolone ( HDMP ) and antithymocyte globulin (ATG). A complete normalization of the haematological data was obtained in one patient, which has persisted now for 10 months. ATG and HDMP seem to provide an alternative mode of treatment of SAA to bone marrow transplantation if there is no histocompatible bone marrow donor available.
The patient suffered from recurrent stridor since the eighth month of life; during the seventh hospitalization at the age of 2 1/2 years laryngeal papillomas were found. Surgical removal of the papillomas was attempted several times. Despite this bronchopulmonary papillomas were seen on chest X-ray films at the age of seven years. After intravenous bleomycin therapy (7 mg/sqm twice weekly for nine weeks) the infiltrates disappeared and the patient has remained free of symptoms til now (18 months later).
BACKGROUND: Osteosarcoma and Ewing's sarcoma are the most frequent malignant bone tumors in children and young adults with relatively poor overall survival rates. METHODS: Between January 1980 and December 1994, 175 children with osteosarcoma and 64 children with Ewing's sarcoma were treated at the author's institution. 22 children had synchronous metastases, 19 patients had a pathologic fracture. Both groups were treated systemically with chemotherapy regimens (COSS and CESS). Local therapy was amputation or tumor resection and endoprosthetic replacement or biological reconstruction with wide or radical resection margins. In case of Ewing's sarcoma in 35 patients postoperative radiation therapy was done. RESULTS: Five-year overall survival rate for osteosarcoma and Ewing's sarcoma patients is about 63 %, ten-year survival rate for osteosarcoma patients is 60.2 %, for Ewing's sarcoma patients 54.5 %. Prognostic factors significantly influencing overall survival rates are tumor response to chemotherapy (p values = 0.0056 and 0.013, respectively), surgical treatment with adequate resection margins (p value = 0.0001 for osteosarcoma patients) and development of postoperative metastases (p value = 0.0001 for both groups). CONCLUSION: For both groups of malignant bone tumors systemic chemotherapy as well as adequate surgical therapy are necessary to reduce the rates of local recurrences and to achieve better survival rates.
BACKGROUND: The treatment of Wilms Tumor is integrated into clinical trials since the 1970's. In contrast to the National Wilms Tumor Study Group (NWTSG) the SIOP trials and studies largely focus on the issue of preoperative therapy to facilitate surgery of a shrunken tumor and to treat metastasis as early as possible. PATIENTS AND METHODS: In the SIOP 93-01/GPOH trial and study 1 020 patients with a newly diagnosed renal tumor were registered. 847 of them had a histological proven Wilms Tumor, of whom 637 were unilateral localized, and 173 tumors had an other histology [40 congenital mesoblastic nephroma (CMN), 51 clear cell sarcoma (CCSK), 24 rhabdoid tumor (RTK) and 58 other tumors]. Preoperative chemotherapy in benign tumors was given to 1.3 % of the patients. The main objective of the trial was the randomized question, if the postoperative two drug chemotherapy for stage I in intermediate risk or anaplasia can be reduced from conventional 3 courses to an experimental 1 course without loss of efficacy. RESULTS: 519 patients with unilateral nonmetastatic Wilms did receive preoperative chemotherapy. The histology in this group of patients was of intermediate risk in 469 (90 %) patients, 14 (3 %) tumors were low risk and 36 (7 %) high risk. The stage distribution of the tumors was stage I in 315 (61 %), stage II N- in 126 (24 %), stage II N+ in 25 (5 %) and stage III in 36 (7 %) patients. In 17 (3 %) patients the tumor stage remained unclear. Tumor volume was measured in 487 patients before and in 402 after preoperative chemotherapy. The median tumor volume did shrink from 353 to 126 ml. The amount of volume reduction depends on the histological subtype. The event free survival (EFS) after 5 years was 91 % for all patients with unilateral Wilms tumor without distant metastasis. Randomisation was done in 43.7 % for stage I patients and there was no difference in EFS for both treatment arms (90 versus 91 %). The EFS is identical for patients with stage I and II N- (0.92), as well as for stage II N+ and III (0.82). The tumor volume after chemotherapy is a prognostic factor for intermediate risk tumors with the exception of epithelial and stromal predominant tumors. These two subtypes often present as large tumors, they do not shrink during preoperative chemotherapy but they still have an excellent prognosis. On the other hand the prognosis of patients with blastemal predominant subtype after preoperative chemotherapy is worse than in any other patient group of intermediate risk tumors. There are less blastemal predominant tumors compared to primary surgery, but they are chemotherapeutic resistant selected by the preoperative chemotherapy. CONCLUSION: Patients with unilateral Wilms tumor without metastasis have an excellent prognosis. The post-operative chemotherapy in stage I can be reduced to 4 weeks without worsening treatment outcome. The reduction of the tumor volume could be identified as a helpful marker for stratification of post-operative treatment. Post-chemotherapy blastemal predominant subtype of Wilms tumor has to be classified as high risk tumor. Focal anaplasia has a better prognosis than diffuse anaplasia and will be classified as intermediate risk tumor.
The observation of constitutional chromosome abnormalities in a one and half year old boy with Wiedemann-Beckwith syndrome (WBS) and hepatoblastoma prompted us to review the currently available literature dealing with this subject. In approximately 500 published cases with complete and incomplete forms of WBS, 42 malignant and 9 benign neoplasms have been described. Malignant tumors, in particular, mainly consisted of nephroblastomas and adrenocortical carcinomas. The patient presented in this paper is the fourth with a hepatoblastoma. The constitutional karyotype was analysed in 84 cases; in 68 of them with banding techniques. Abnormalities have only been detected in 11 patients. A 47;XXY karyotype, an inversion of chromosome 2, a partial duplication of the long arm of chromosome 8 and reciprocal translocations t(11;22) and t(X;1), respectively, have been observed in one case each. Individually differing changes in the remaining six cases led to a common triplication of the region 11p15. This triplication has also been the only abnormality, which has so far been reported in one out of six investigated WBS patients with a tumor. Cytogenetic analysis in our case revealed an interstitial deletion of the short arm of chromosome 11 and a complete pericentric inversion of the chromosome 9 heterochromatin block. The breakpoints of the deletion, del(11) (p11.1p11.2), are located proximal of those (11p15) reported in anomalies of other WBS patients, as well as proximal of those involved in patients with the aniridia/Wilm's tumor complex (11p13-11p14). Inversion of the heterochromatin of chromosome 9 has been recognized as a normal variant, which generally remains without phenotypic effects.(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND: Owing to twenty years of multicentric interdisciplinary cooperation, the COSS group has been able to collect data on a large group of osteosarcoma patients treated by neoadjuvant therapy. This paper reviews results achieved in patients with localized extremity tumors. PATIENTS AND METHODS INCLUSION CRITERIA: Registration into a completed neoadjuvant COSS-Study. Histologically confirmed, primary, localized, high-grade, central osteosarcoma of an extremity; age < 40 years; no pretreatment; interval diagnosis to chemotherapy < or = 3 weeks; no severe comorbidity. Chemotherapy: HD-methotrexate +/- doxorubicin +/- cisplatin +/- ifosfamide +/- BCD. Scheduled local therapy: Surgery. RESULTS: 925 evaluable patients from 101 institutions. Median age 15 years, m:f 1.4:1. Primary site: femur 510, tibia 251, humerus 100, fibula 51, other 13. Tumor-size < 1/3 of the involved bone 616, > or = 1/3 304. Definitive surgery in 903/925 cases, 443 limb salvage procedures. Good response (> 90% necrosis) in 469/806 (58.2%) evaluated tumors. Median follow-up for surviving patients: 5.42 years. Actuarial survival after 5 and 10 years: 72.5% (95%-CI 69.3-75.7) and 66.3% (62.5-70.0), relapse-free 62.1% (58.7-65.4) and 59.4% (55.8-63.0). 683/925 alive (601 first remission), 242 deceased (212 tumor progression, 30 other causes). 66.2% (97.3%) of all relapses within 2 (5) years. Prognosis correlates with tumor-size (< vs. > or = 1/3: 69.9% vs. 58.3% at 10 years) and -site (tibia: 74.2%, humerus: 54.5%) and -response (good vs. poor: 78.2% vs. 52.5%) (all p < 0.01). Actuarial 10-year survival by response grading I-VI according to Salzer-Kuntschik 80.9%, 82.8%, 71.1%, 60.7%, 47.7%, 27.3%. COSS-studies with preoperative 4-drug therapy more efficacious than less aggressive protocols. No impact of doxorubicin scheduling (sequential: rapid vs. 48 h-continuous infusion) or cisplatin scheduling (randomized: 5 h vs. 72 h-infusion) on prognosis detected. CONCLUSIONS: Intensive multiagent chemotherapy and delayed surgery for localized extremity osteosarcoma led to excellent oncologic results in the COSS-studies. Tumor-size, -site, and -response as well as the intensity of upfront chemotherapy correlated with outcome. Giving doxorubicin and cisplatin by continuous infusions did not result in discernible prognostic disadvantages.
BACKGROUND: Ewing tumor patients' outcome is 50% to 60% with current treatment strategies. Questions concerning toxicity and secondary malignancies are of increasing importance. PATIENTS AND METHODS: 631 patients were registered with the German EICESS study center of the European Intergroup Cooperative Ewing's Sarcoma Study, 369 patients were randomized. Treatment apart from local therapy consisted of 14 courses of Vincristine, Actinomycin D, Cyclophosphamide or Ifosfamide, Adriamycin (Doxorubicin), with or without Etoposide. First results concerning event-free survival (EFS), toxicity, and the rate of secondary malignancies three years after diagnosis are presented. RESULTS: Three year EFS was 0.66 for patients with localized tumors, 0.43 for patients with primary pulmonary/pleural metastases, and 0.29 for patients with other metastases, respectively. Large tumor volume or pelvic site, especially if inoperable, were adverse prognostic factors. Both histological and MRT-defined response were positively correlated to outcome. Up to 67% of patients experienced WHO grade IV toxicity, mostly related to bone marrow depression. The treatment related mortality was 1% (6/631). Until 15.02.1999, six of 687 patients have suffered secondary malignancies, two of six after (additional) myeloablative therapy. CONCLUSIONS: EICESS 92 treatment is toxic, but manageable and compares favorably to international results. New strategies must be sought for certain risk groups of patients.
BACKGROUND: Patients (pts) with primary metastatic Ewing tumours (ET) have a poor prognosis for event free survival (EFS) compared to pts with localised disease. Following relapse the prognosis is extremely poor. Therefore these primary metastatic and relapsed pts were piloted for high dose therapy (HDT) for the last years. PATIENTS AND METHODS: Between April 1984 and May 1997, 131 ET pts who underwent HDT were registered in the German CESS/EICESS office: 79 pts with primary metastases and 52 pts with relapsed tumours. After induction therapy, consisting of chemotherapy and local therapy, pts received high dose regimens, mainly based on melphalan and/or etoposide (92%). Stem cell rescue was applied from allogeneic bone marrow (n = 13), autologous bone marrow (n = 17), or peripheral blood stem cells (n = 95). The date of analysis was September 1st, 1998. Outcome was calculated by Kaplan-Meier-analyses. RESULTS: The median time under study since high dose therapy was 3.7 years. 35/131 pts (26.7%) were in continuous complete remission, 80/131 pts (61.1%) had relapsed or progressed, 11/131 pts (8.4%) died of complications and 5/131 pts (3.8%) presented with secondary malignancies. For the total group of primary metastatic pts, EFS five years after diagnosis was 19% for pts with HDT and 27% for those without (p = 0.9209). The subgroup of pts with primary lung and bone metastases seemed to benefit from HDT (EFS five years after diagnosis: 34% versus 5%, p = 0.0001). Outcome of pts with an early ET relapse (< 2 years) was also improved by HDT (EFS four years after relapse: 17% versus 2%, p = 0.0001). CONCLUSIONS: The total group of primary metastatic ET pts showed no obvious benefit from HDT, based on melphalan and/or etoposide. Pts with metastases to multiple organ systems, and early relapse seemed to benefit from HDT. The value of HDT should be assessed in prospective clinical trials.
The congenital hypoplastic-dysplastic kidney is characterized by a significant reduction of renal mass, an abnormal parenchymal differentiation and is associated with anomalies of the whole urinary tract. Not much is known about the ability for regeneration in such a kidney. We report on a 2 year 11 months old boy with an anaplastic Wilms tumor of the left kidney, in whom after tumor-nephrectomy an unexpected functional and sonographically documented morphological regeneration of the contralateral hypoplastic-dysplastic kidney occurred. The regeneration of this kidney is especially notable, because it occurred during nephrotoxic chemotherapy and radiotherapy.
AIMS: A multivariate analysis was performed to evaluate the impact of various prospectively evaluated risk factors. PATIENTS AND METHODS: From January 1987 to December 1993, 120 patients were registered in the study. 108/120 patients were eligible. There were 49 girls and 59 boys with a median age at diagnosis of 14 months (range, 0 to 224 months). Patients were classified according to the Evans classification system. LDH, NSE, Ferritin, N-myc amplification, 1p-deletion and ploidy were evaluated at diagnosis. Treatment intensity was based on the results of primary surgery: surgery only for 22 (20%) stage I and IIA patients (macroscopic residue without lymph node involvement), the 9 IIB patients (8,5%) (macroscopic residue with lymph node involvement) had mild chemotherapy in addition (6 x VCR/CYC) and elective radiation (Rx). Stage III patients were divided into 2 groups: IIIA patients (n = 17/16%) had to have ferritin levels under 300 micrograms/ml, NSE lower than 100 ng/ml and age below 2 years at diagnosis and received 6 alternating cycles of DAMO/ MVDOC. If one of these three criteria was not fulfilled, patients were assigned to the more intensive treatment arm stage IIIB (n = 12/11%), i.e. 9 alternating cycles of DAMO/MVDOC/IPE. Stage IV pts (n = 35/32.5%) received 8 MVDOC/IPE cycles and 20 patients received megatherapy followed by stem cell reinfusion in addition. 13 stage IVs patients (12%) were registered and had elective VCR/CYC and/or liver radiation in case of poor clinical condition. The median observation time is 4.2 years (range, 1 to 7.5). RESULTS: The survival rate at 3 years was excellent for localized disease and stage IVs with survival rates of 100% for stage I/IIA and 92% for stage IVs. Stage IIIA patients had an EFS rate of 81% whereas stage IIB patients achieved only 69%. Stage IV patients reached 51%, however outcome was especially poor for stage IIIB patients (20%) due to treatment related toxicities. The toxic death rate in the study was 13% (2 surgical deaths, 8 infections, 4 multiple organ failures). Univariate analysis demonstrated the following significant unfavorable risk factors: age over 1 year at diagnosis (58/108 pts, p = 0.006), NSE > 100 ng/ml (26/95 pts, p < 0.0001), Ferritin > 300 ng/ml (19/98 pts, p = 0.007), LDH > 300 (400) U/L, 51/87 pts, p = 0.004), presence of N-myc amplification (17/59 pts, p = 0.001), deletion of the short arm of chromosome 1 (19/74 pts, p < 0.0001) and di/tetraploidy (32/72 pts, p = 0.008). The power of these factors was even stronger in patients with localized disease whereas no significant prediction was observed for stage IV patients. Furthermore a significant correlation of the serological (NSE, ferritin, LDH) and biological factors (N-myc, deletion 1p, di/tetraploidy) was detected in this study. Only NSE was identified as an independent prognostic factor (p = 0.018) whereas no independent factor could be identified within the 3 biological parameters due to their high correlations (Kendall's tau for N-myc and deletion 1p:0.7). However, N-myc (p = 0.005) as well as deletion 1p (p = 0.01) were found significantly more important than di/tetraploidy. CONCLUSIONS: Biological classification of neuroblastomas should be mandatory and be the prerequisite for any risk adapted treatment. One serological and 2 biological factors could be a good standard evaluation to identify neuroblastoma patients at risk.
Transplantations to restore the hematopoietic system were originally performed with cells from the bone marrow (BM) (20) which was considered the only cell source comprising repopulating progenitor cells. The discovery that chemotherapy induced the mobilization of CD34+ cells into the peripheral blood (PB) (14) gave rise to the successful autologous transplantation of PBSC (1, 13). Also cord blood (CB) was found to contain considerable numbers of "stem cells", and to date at least 42 allogeneic transplantations have been performed with this cell source (22, J. Wagner, personal communication). Further investigations led to the successful autologous transplantation of positively selected CD34+ cells from BM and PB (18), and the latest results indicate that it is promising to transplant purified CD34+ cells obtained from cytokine-stimulated donors (4, 10, 15-16). Despite such achievements it remains unclear how many "stem cells" are required per kg of the recipient and how they are phenotypically characterized. In this communication we give examples of typical differences observed by flow cytometry and clonogenic assay between the CD34+ cells contained in the different cell sources. They may explain why it is not sufficient only to analyze the CD34+ cell populations which may represent progenitors of different lineages as well as of various states of differentiation. CB CD34+ cells are early myeloid progenitor cells with the highest incidence of CFU-mix among the three cell sources. They have a high proliferative potential in vitro. They hardly coexpress B cell antigens and they are partially negative for CD38.(ABSTRACT TRUNCATED AT 250 WORDS)
We have performed in situ hybridization (ISH) studies predominantly on paraffin sections and on isolated nuclei of 22 pediatric germ cell tumors (GCTs) from 18 patients including 4 recurrences from three patients. In addition, we performed conventional cytogenetic analyses in three tumor samples. Because reports on cytogenetic studies in pediatric GCTs are scarce we focused our studies on those chromosome abnormalities frequently observed in adult GCTs. These included numeric and structural abnormalities of chromosomes 1 and 12 (e.g. isochromosome 12p) and numeric deviations of chromosomes 8, 10, X and Y. The histological subsets of the tumors investigated included two dysgerminomas (DGE), one seminoma (SE), one combined seminoma, two embryonal carcinomas (EC), two recurrent ECs, six pure yolk sac tumors (YST), five combined teratomas, one immature teratoma (IT) and two recurrences of IT, and three differentiated teratomas (TD). Similar to the GCTs in adults, additional copies of chromosome 12 were the most frequently observed numeric abnormalities. The analysis of two paraffin-embedded tumors suggested that changes in the size of the pericentromeric hybridization signals of chromosome 12 may be attributed to the presence of i(12)(p10). This was confirmed following the karyotype analysis of one EC which unequivocally revealed the presence of two i(12)(p10). Interestingly, using these probes, no chromosomal abnormalities were found in the pure TD or in the TD cells of mixed tumors containing a YST component. In the YST portion, however, the 1p deletions and/or numeric chromosome changes were present. Surprisingly, deletions at the short arm of chromosome 1, del(1)(p36.3), were frequently observed in malignant pediatric GCTs and were the sole abnormality detected in one case.(ABSTRACT TRUNCATED AT 250 WORDS)