Testicular germ cell tumors in adolescents - results of the protocol MAHO 98 and the identification of good risk patients.

BACKGROUND: In adolescents aged 10-15 years germ cell tumors of the testis (TGCT) are rare and information for a risk adapted therapy limited. AIMS OF THE STUDY: The protocol MAHO 98 for patients (pts) with TGCTs is stratified according to age, stage and histology. Pts ≥ 10 years received after tumororchiectomy 2 courses (crs) PVB and restaging. Residual tumor was resected and therapy continued in regard to inital stage and response. Chemotherapy: PVB: cisplatin (20 mg/m²/day 1-5), vinblastine (3 mg/m²/day 1+2), and bleomycin (15 U/m²/day 1-3). For consolidation 1 crs PVB has been given to stage II patients with CR. In case of PR, 2 crs PEB (vinblastine substituted by etoposide 100 mg/m²/day 1-3) or relapse 3 crs PEI (bleomycin substituted by ifosfamide 1 500 mg/m²/day 1-5) were given. RESULTS: Between Jan 1998 and Dec 2005, 34 pts (≥ 10 year) were registered, 31 fulfilled the inclusion criteria. Median age: 15;6 years; months (range 13;5-20;2 ). Lugano staging: IA n=14, IB n=2, IC n=3, IIA n=4, IIB n=6, IIC n=1, IIIC n=1. The stage IIIC pt received preoperative chemotherapy, all other pts had tumororchiectomy first. Residual tumor after 2 crs PVB was detected in 4 pts and was resected. Late relapses occurred in 2 pts and were cured by additional therapy. All patients are surviving. CONCLUSION: Young patients with TGCT stage I and II have an excellent prognosis and further reduction of therapy has to be considered.

Testicular germ cell tumors in boys <10 years: results of the protocol MAHO 98 in respect to surgery and watch & wait strategy.

UNLABELLED: In 1982 the GPOH opened the 1st protocol for germ cell tumors (GCTs) of the testis (MAHO 82). Here the results of the 5th version (MAHO 98) will be offered for boys <10 year of age.In MAHO 98 watch and wait (w&w) strategy after inguinal tumororchiectomy was widened from 2 to 10-year-old boys with YST stage IA (group I); other invasive measures were omitted. Thus the prognostic impact of a non-recommended surgery like transscrotal operation +/- conventional biopsy (group II) can be evaluated.Clinical diagnosis and staging by ultrasound and tumor marker. In blurry cases, a frozen section was recommended to confirm the diagnosis by histology intraoperatively. Indications for adjuvant chemotherapy were: YST stage IA without elevated AFP, YST stage>IA and all mixed malignant GCTs.From 1998 till 2005 128 boys <10 years with a testicular GCT were registered. HISTOLOGY: YST n=76, teratoma n=46, mixed malignant GCT n=6. Tumor stage IA: n=101. All teratoma patients survive event-free. At all, only 19/82 patients with a malignant GCT received chemotherapy including 5 patients with a tumor progress after w&w (2/49 group I and 3/15 group II patients, respectively) and 1 patient (YST IIIA) with relapse after adjuvant chemotherapy. Transscrotal surgery (n=18) or tumorenucleation (n=6) remained without event. Indeed all patients survived.Prognosis of boys <10 year with a testicular GCT is excellent as ~80% will be cured by high inguinal tumororchiectomy alone. w&w is feasible and safe even after not recommended surgery if suitable follow-up is assured at least in stage IA cases.

Telemicroscopic conferences for children of the Perm territory with suspected or proven malignant solid tumors.

BACKGROUND: Malignant solid tumors are rare events in childhood and adolescence. Therefore central review of the histology and standardized grading are requested for accurate risk estimation and facilitate a tumor risk adapted treatment. AIMS OF THE STUDY: To abandon the time consuming transportation of tumor material over long distances to the specialized institution by implementation of an internet based consultation system. METHODS: A microscope combined with a videocamera (situated in Perm) and the personal computers of each of 4 cooperating institutions (in Perm, Kiel, Koeln, Duesseldorf) has been equipped with the special software Mikroskopkonferenz. Additional videocameras allow the transmission of the cooperators to each other. Headsets are used to avoid reecho. As a prerequisite an internet connection with a 54 KBits capacity has to be provided. RESULTS: Between January and December 2009, 26 children (median age 2; 5 years, 12 females and 14 males) with suspected or proven malignant solid tumors have been discussed in 11 telemicroscopic conferences by international cooperators. CONCLUSION: This cooperation demonstrates the proof of principle to obtain second opinions in short time over far distances for seldom diseases on a scientific level.

[Quality improvement of multiple choice examinations: in psychiatry, psychosomatic medicine, psychotherapy, and neurology]. / Qualitätsverbesserung von Multiple-Choice-Prüfungen: In Psychiatrie, Psychosomatik, Psychotherapie und Neurologie.

We describe a continuous improvement process in planning, performance, and evaluation of multiple choice examination questions in psychiatry, neurology, psychosomatic medicine, and psychotherapy. We analyzed 640 multiple choice questions of 1,419 students during a period of 4 years. Crucial changes concerned the abolishment of problematic question types, implementation of validated new question formats, extension of case-based questions, elongation of question stems, quantitative evaluation of item difficulty, discriminatory value, and the introduction of a peer review system. Consequences of these improvements were greater item difficulty (average 18%) and discriminatory value (average 67%) and reduced post hoc analysis times. Introduction of peer reviews resulted in longer preparation time, which was however appreciated by the peers due to a clear improvement in item quality.

No prognostic effect of additional chromosomal abnormalities in children with acute lymphoblastic leukemia and 11q23 abnormalities.

This study characterized the additional chromosomal abnormalities (ACA) associated with 11q23 rearrangements in 450 infants and children with acute lymphoblastic leukemia (ALL) and examined the impact of these ACA on survival. Overall, 213 (47%) cases had ACA but the incidence varied according to patient age and 11q23 subgroup. Infants and patients with t(4;11)(q21;q23) had the lowest incidence of ACA (50/182 (27%) and 57/216 (26%) respectively), whereas patients with del(11)(q23) had the highest incidence (66/93 (71%)). Del(11)(q23) abnormalities were heterogeneous and occasionally secondary to t(9;22)(q34;q11.2). Thus, patients with del(11)(q23) comprised a separate biological entity, which was clearly distinct from those with an 11q23 translocation. The most frequent specific ACA were trisomy X (n = 38), abnormal 12p (n = 32), abnormal 9p (n = 28) and del(6q) (n = 19). The presence of ACA did not change the 5 year event-free survival estimates among children (56% (95% Cl 46-65%) vs 62% (54-69%)) or infants (22% (15-29%) vs 18% (9-29%)), nor when the different 11q23 subgroups were analyzed separately. This study has conclusively demonstrated that there is no prognostic effect of secondary chromosomal changes in association with 11q23 abnormalities in childhood ALL. However, characterization of these ACA is important to determine their potential role in initiation of MLL driven leukemogenesis.

Mutation of the p53 gene in neuroblastoma and its relationship with N-myc amplification.

Mutation of the p53 tumor suppressor gene frequently occurs in a variety of tumors including lung, breast, gastrointestinal, and brain, as well as lymphomas-leukemias. Neuroblastoma, one of the most common solid tumors in childhood, often has amplification of the N-myc gene. We examined for mutations of the p53 tumor suppressor gene by single-strand conformational polymorphism using polymerase chain reaction products and direct sequencing method in neuroblastoma; in addition, we assessed the relationship between p53 mutation and N-myc gene amplification in the disease. Of 86 DNA samples from patients with neuroblastoma, two mutations (2%) were found in the coding region of the p53 gene. Each mutation caused a substitution of amino acid residues. One mutation was located in exon 5, and another was in exon 6. N-myc gene was amplified in 26% of the samples. No p53 mutations were found in neuroblastoma samples with N-myc amplification. In the two individuals, p53 mutations appeared as their disease became more progressive. The neurofibromatosis 1 (NF1) gene is frequently abnormal in another neural disorder, neurofibromatosis type 1; in addition, a potential mutational hot spot of NF1 at lysine at codon 1423 has been identified in several types of tumors. Using single-strand conformational polymorphism, we were unable to detect an abnormality in this region of NF1 in 50 samples of neuroblastoma. The data suggest that p53 mutations occasionally are associated with progression of neuroblastomas, and tumorigenetic influences of mutant p53 may differ from those of N-myc.

The accumulation of neutral red in illuminated thylakoids.

Thylakoids isolated from spinach (Spinacia oleracea L.) bind only a small fraction of neutral red in the dark whereas they accumulate large amounts of the protonated dye in their inner space under light. Light-induced neutral red uptake depends on the size of the proton gradient across the thylakoid membrane but does not follow the mechanism established for amines. Instead, the correlation between pH gradient and neutral red uptake can be predicted quantitatively assuming that protonated neutral red is accumulated mainly as dimer species. Under appropriate conditions, accumulation of protonated neutral red in the inner thylakoid space is proportional to an absorbance increase at 520 nm. This 520-nm change can be used for the continuous measurement of pH changes in thylakoids during steady-state illumination.

Carotenoid transformations underlying the blue absorbance change in flashed leaves during the induction of oxygen evolution.

The blue absorbance change occurring in flashed bean (Phaseolus vulgaris L.) leaves when exposed to continuous light (first observed by Strasser; Strasser, R.J. (1973) Arch. Int. Physiol. Biochem. 81, 935--955) is caused by the conversion of the following xanthophylls: violaxanthine leads to antheraxanthine leads to zeaxanthine. This conclusion is derived from the simultaneous occurrence of both reactions: (a) In flashed leaves, blue absorbance change and xanthophyll conversion take place under strong (2 mW . cm-2) but not under weak (0.02 mW . cm-2) white light. (b) In chloroplasts isolated from flashed leaves, the blue absorbance change occurs in the dark under conditions that also induce the xanthophyll conversion. (c) Blue absorbance change and xanthophyll conversion are both inhibited by dithiothreitol. In addition, the light-induced blue absorbance change is reversed in the dark if aerobic conditions are maintained, i.e. under conditions that in normal leaves favor the reversal of the above reaction sequence. The significance of the xanthophyll conversion is discussed in relation to other phenomena occurring in flashed leaves after exposure to continuous illumination.

Prognostic value of tumor size, metastases, extension into bone, and increased tumor marker in children with malignant sacrococcygeal germ cell tumors: a prospective evaluation of 71 patients treated in the German cooperative protocols Maligne Keimzelltumoren (MAKEI) 83/86 and MAKEI 89.

PURPOSE: To evaluate the prognostic value of metastases, extension into bone, and alpha-fetoprotein (AFP) elevation in children with malignant sacrococcygeal germ cell tumors (GCTs) prospectively collected in two cooperative Maligne Keimzelltumoren (MAKEI) protocols (83/86 and 89). PATIENTS AND METHODS: Between October 1983 and October 1995, 76 of 210 registered patients with sacrococcygeal primaries presented either with pure yolk sac tumor, embryonal carcinoma (EC), or yolk sac tumor and EC mixed with immature and mature teratoma elements. Stages T1 and T2 disease were diagnosed in 15 and 61 children, respectively, 41 patients had metastases, and 35 children presented with extension into bone. At diagnosis, 22 children had an AFP elevation of less than 10,000 ng/mL. Thirty-six children showed an AFP level between 10,000 and 100,000 ng/mL, and 12 patients had values of greater than 100,000 ng/mL. Five patients died of complication during treatment and were excluded from further evaluation. Seventy-one patients could be analyzed. RESULTS: The 5-year relapse-free survival rate (RFS, Kaplan-Meier) was 0.76 +/- 0.03 (54 of 71 patients; median observation time, 54 months after diagnosis). The RFS of patients with and without metastases was different, but not significantly so (0.71 v 0.82). The outcome of patients with extension into bone (n = 31) and without this extension (n = 40) was 0.71 versus 0.80 (RFS, 5 years). Above-normal AFP level had no prognostic significance (P =.52). CONCLUSION: In children with malignant sacrococcygeal GCTs treated with an intensive, short-interval, platinum-based regimen, the stage, extent of metastases, extension into bone, and AFP level had no prognostic significance.

Primary mediastinal germ cell tumors in children and adolescents: results of the German cooperative protocols MAKEI 83/86, 89, and 96.

PURPOSE: To evaluate children and adolescents with primary mediastinal teratoma and malignant germ cell tumors (GCTs). PATIENTS AND METHODS: Forty-seven patients from the German nontesticular GCT studies were analyzed (median age, 2.5 years; range, neonate to 17 years). Teratoma (n = 21) were resected, and no adjuvant treatment was given. Malignant GCTs (n = 26) were treated with cisplatin-based chemotherapy and resection. Three of 26 patients underwent radiotherapy. RESULTS: In all patients with teratoma, tumor markers were normal. Surgery of teratoma was complete in 17 of 21 patients and microscopically incomplete in four of 21 patients, and we observed no relapse after a median follow-up of 29 months. In 23 of 26 patients with malignant GCTs, alpha-fetoprotein and/or beta-human chorionic gonadotropin were elevated. Twelve of 26 patients received adjuvant chemotherapy after initial resection, which was complete in six of 12 patients, whereas delayed resection after preoperative chemotherapy was complete in 10 of 11 patients (P =.03). Four of six patients underwent second-look thoracotomy after incomplete primary surgery. Three of 26 patients did not undergo tumor resection. The final completeness of resection was the strongest prognostic indicator (event-free survival ¿EFS, 0.94 +/- 0.06 v 0.42 +/- 0.33; P <.002). Local stage and distant metastases were not prognostically significant at the.05 level. For all malignant GCTs, the 5-year survival rate was 0.87 +/- 0.05 (median follow-up, 51 months), with an EFS of 0.83 +/- 0.05. CONCLUSION: The prognosis of mediastinal teratoma is excellent after complete or microscopically incomplete resection. In children with malignant GCT, the prognosis is favorable with a therapeutic strategy of delayed resection after preoperative chemotherapy. In most children, the diagnosis can be based on elevated tumor markers and imaging. Biopsy is indicated in nonsecreting GCT.

Radiation therapy for intracranial germinoma: results of the German cooperative prospective trials MAKEI 83/86/89.

PURPOSE: A multicenter prospective trial was conducted (Maligue Keimzelltümoren [MAKEI] 83/86/89) to assess outcome in intracranial germinoma after treatment with radiotherapy alone at reduced doses. PATIENTS AND METHODS: Between 1983 and 1993, 60 patients with histologically (n = 58) or cytologically (n = 2) confirmed germinoma were enrolled onto the study. Patients received radiotherapy alone (craniospinal axis/local boost). In the MAKEI 83/86 study (involving 11 patients), the dose to the craniospinal axis was 36 Gy and the dose to the tumor region was 14 Gy. In the MAKEI 89 study (involving 49 patients), doses were 30 and 15 Gy, respectively. RESULTS: Median patient age was 13 years (range, 6 to 31 years). Complete remission was achieved in all patients. The estimated (Kaplan-Meier) 5-year relapse-free survival rate was 91.0% +/- 3.9% at a mean follow-up of 59.5 months (range, 3 to 180 months); the estimated overall survival rate was 93.7% +/- 3.6%. Relapse occurred in five patients 10 to 33 months (mean, 18.4 months) after diagnosis (one patient developed a spinal canal metastasis and underwent salvage radiotherapy and chemotherapy; four patients had metastases outside the CNS and underwent salvage chemotherapy alone). Four patients died: one died from disease, two died from therapy-related complications, and one committed suicide. Acute complications with long-lasting sequelae were tumor or surgery related (three cases of blindness, six of reduced vision, two of hemiparesis). Psychosocial development was normal in the majority of patients. CONCLUSION: Radiotherapy directed toward the craniospinal axis or tumor site alone at decreased dose levels is effective. To reduce the risk of late side effects, further attempts to decrease total doses are justified. In cases of recurrent disease, chemotherapy administered outside the CNS is the treatment of choice.

Results of treatment for soft tissue sarcoma in childhood and adolescence: a final report of the German Cooperative Soft Tissue Sarcoma Study CWS-86.

PURPOSE: The goal of the second German Soft Tissue Sarcoma Study CWS-86 (1985 to 1990) was to improve the prognosis in children and adolescents with soft tissue sarcoma by means of a clinical trial comprising intensive chemotherapy and risk-adapted local therapy. PATIENTS AND METHODS: There were 372 eligible patients. A staging system based on the postsurgical extent of disease was used. Chemotherapy consisted of vincristine, dactinomycin, doxorubicin, and ifosfamide. Radiotherapy was administered early at 10 to 13 weeks simultaneously with the second chemotherapy cycle (32 Gy or 54. 4 Gy). The single dose was reduced to 1.6 Gy and given twice daily (accelerated hyperfractionation). RESULTS: The event-free survival (EFS) and overall survival rates at 5 years were 59% +/- 3% and 69% +/- 3%, respectively. The 5-year EFS rate according to stage was as follows: stage I, 83% +/- 5%; stage II, 69% +/- 6%; stage III, 57% +/- 4%; and stage IV, 19% +/- 6%. The outcome for patients with stage III disease who required radiotherapy was much better in the CWS-86 study compared with the CWS-81 study (5-year EFS, 60% +/- 5% v 44% +/- 6%; P =.053). The most common treatment failure was isolated local relapse, with 14% of patients relapsing at the primary tumor site. CONCLUSION: The improved design of the study incorporating risk-adapted radiotherapy allowed treatment to be reduced for selected groups of patients without compromising survival.

Multimodal treatment of malignant sacrococcygeal germ cell tumors: a prospective analysis of 66 patients of the German cooperative protocols MAKEI 83/86 and 89.

PURPOSE: To evaluate a multimodal approach including surgery and cisplatinum chemotherapy for treatment of children with malignant sacrococcygeal germ cell tumors (GCT) and to compare adjuvant and neoadjuvant strategies in advanced tumors. PATIENTS AND METHODS: Between 1983 and 1995, 71 patients with malignant sacrococcygeal GCT were prospectively enrolled onto the German protocols for nontesticular GCT Maligne Keimzelltumoren 83/86 and 89. Five patients who received no chemotherapy (n = 2) or nonplatinum chemotherapy (n = 2) or who did not undergo tumor resection (n = 1) were excluded from this analysis. Among the 66 patients analyzed were 14 boys and 52 girls. The median age was 17.4 months (range, 7 months to 119 months). Median follow-up was 79 months (range, 4 months to 145 months). RESULTS: Fifty-two patients presented with locally advanced stage T2 tumors, and 30 patients had distant metastases at diagnosis. Patients received a median of eight cycles (range, four to nine cycles) of cisplatinum-based chemotherapy. Thirty-five patients underwent tumor resection at diagnosis and received adjuvant cisplatinum-based chemotherapy (group A). Thirty-one patients received up-front chemotherapy followed by delayed tumor resection (group B). Group B included more metastatic tumors than group A (group B, 19 of 31 patients; group A, 11 of 35 patients, P =.01). Preoperative chemotherapy facilitated complete tumor resections (group B, 20 of 31 patients; group A, five of 35 patients, P <.001) and avoided second-look surgery. Metastases at diagnosis and completeness of the first attempt of tumor resection were significant prognostic predictors; however, metastases were not predictive for patients treated with up-front chemotherapy. At 5 years follow-up, event-free survival was 0.76 +/- 0.05 (50 of 66 patients), and overall survival was 0.81 +/- 0.05 (54 of 66 patients). Four patients died as a result of therapy-related complications, and eight patients died of their tumors. Patients with locally advanced and metastatic tumors (T2b M1) fared better with neoadjuvant treatment [overall survival: 0.83 +/- 0.09 (16 of 19 patients) versus 0.45 +/- 0.15 (five of 11 patients), P =.01]. CONCLUSION: Even locally advanced and metastatic sacrococcygeal GCT can be successfully treated with up-front cisplatinum-based chemotherapy followed by delayed but complete tumor resection.

Ovarian sex cord-stromal tumors in children and adolescents.

PURPOSE: To develop diagnostic standards and a risk-adapted therapeutic strategy for ovarian sex cord-stromal tumors (OSCST). PATIENTS AND METHODS: Fifty-four patients were prospectively enrolled as follow-up patients onto the German Maligne Keimzelltumoren protocols. Surgical protocols and histopathology were reviewed centrally (53 patients with complete data). Surgery included ovariectomy in 18 patients, salpingo-ovariectomy in 34 patients, and hysterectomy in one patient. Patients with stage IA tumors were followed-up at regular intervals, whereas nine patients with stage IC and six patients with stage II to III tumors were treated with cisplatin-based chemotherapy. RESULTS: International Federation of Gynecology and Obstetrics stage was IA in 27 patients, IC in 21 patients, II in three patients, and III in three patients. After a median follow-up of 59 months (range, 6 to 193 months), event-free survival +/- SD was 0.86 +/- 0.05 (47 of 54 patients) and overall survival was 0.89 +/- 0.05 (49 of 54 patients). Prognosis correlated with stage (event-free survival +/- SD: IA, 1.0 [27 of 27 patients]; IC, 0.76 +/- 0.09 [16 of 21 patients]; and II/III, 0.67 +/- 0.19 [four of six patients]; P =.02). Ten of 15 patients treated with chemotherapy, including four of six stage II to III patients, are alive after a median follow-up of 33 months. CONCLUSION: On the basis of a standardized clinical and histopathologic assessment, risk-adapted therapeutic strategies for OSCST can be evaluated. Considering our experience, we would recommend that stage IA tumors be followed up at regular intervals, whereas we would recommend cisplatin-based chemotherapy in stage IC tumors with preoperative rupture or malignant ascites, especially those with high mitotic activity. Finally, cisplatin-based chemotherapy also seems to be effective in advanced-stage tumors.

Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86.

PURPOSE: Cooperative Ewing's Sarcoma Study (CESS) 86 aimed at improving event-free survival (EFS) in patients with high-risk localized Ewing tumor of bone. PATIENTS AND METHODS: We analyzed 301 patients recruited from January 1986 to July 1991 (60% male; median age 15 years). Tumors of volume >100 mL and/or at central-axis sites qualified patients for "high risk" (HR, n = 241), and small extremity lesions for "standard risk" (SR, n = 52). Standard-risk patients received 12 courses of vincristine, cyclophosphamide, and doxorubicin alternating with actinomycin D (VACA); HR patients received ifosfamide instead of cyclophosphamide (VAIA). Tumor sites were pelvis (27%), other central axis (28%), femur (19%), or other extremity (26%). The initial tumor volume was <100 mL in 33% of cases and > or =100 mL in 67%. Local therapy was surgery (23%), surgery plus radiotherapy (49%), or radiotherapy alone (28%). Event-free survival rates were estimated by Kaplan-Meier analyses, comparisons were done by log-rank test, and risk factors were analyzed by Cox models. RESULTS: On May 1, 1999 (median time under study, 133 months), the 10-year EFS was 0.52. Event-free survival did not differ between SR-VACA (0.52) and HR-VAIA (0.51, P =.92). Tumor volume of >200 mL (EFS, 0.36 v 0.63 for smaller tumors; P =.0001) and poor histologic response (EFS, 0.38 v 0.64 for good responders; P =.0007) had negative impacts on EFS. In multivariate analyses, small tumor volumes of <200 mL, good histologic response, and VAIA chemotherapy augured for fair outcome. Six of 301 patients (2%) died under treatment, and four patients (1.3%) developed second malignancies. CONCLUSION: Fifty-two percent of CESS 86 patients survived after risk-adapted therapy. High-risk patients seem to have benefited from intensified treatment that incorporated ifosfamide.

Patient stratification based on prednisolone-vincristine-asparaginase resistance profiles in children with acute lymphoblastic leukemia.

PURPOSE: To confirm the prognostic value of a drug resistance profile combining prednisolone, vincristine, and l-asparaginase (PVA) cytotoxicity in an independent group of children with acute lymphoblastic leukemia (ALL) treated with a different protocol and analyzed at longer follow-up compared with our previous study of patients treated according to the Dutch Childhood Leukemia Study Group (DCLSG) ALL VII/VIII protocol. PATIENTS AND METHODS: Drug resistance profiles were determined in 202 children (aged 1 to 18 years) with newly diagnosed ALL who were treated according to the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL)-92 protocol. RESULTS: At a median follow-up of 6.2 years (range, 4.1 to 9.3 years), the 5-year disease-free survival probability (pDFS) rate +/- SE was 69% +/- 7.0%, 83% +/- 4.4%, and 84% +/- 6.8% for patients with resistant (PVA score 7 to 9), intermediate-sensitive (PVA score 5 to 6), and sensitive (SPVA score 3 to 4) profiles, respectively (sensitive and intermediate-sensitive v resistant, P

Co-operative study group for childhood acute lymphoblastic leukemia (COALL): long-term follow-up of trials 82, 85, 89 and 92.

The German Co-operative Study Group COALL for treatment of acute lymphoblastic leukemia (ALL) in childhood started the first trial in 1980. This report gives an overview of the long-term results of the four consecutive studies COALL-82, COALL-85, COALL-89 and COALL-92. Besides improvement in long-term survival major objectives were reduction of treatment-related toxicity by transferring asparaginase (ASP) from induction therapy to intensive phase and omitting CNS irradiation by stepwise increase of the initial white blood count (WBC) up to 50 x 10(9)/l (exception T-ALL) as criterion for irradiation. In study COALL-85 in high risk patients slow vs rapid rotational treatment was randomized. In study COALL-92 initial response to daunorubicin (DNR) as a 1-h vs 24-h infusion and its prognostic value was investigated. Furthermore, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) were randomized in maintenance treatment. In total, 1191 eligible patients were enrolled. Induction treatment without ASP has been shown to be as effective and less hazardous than the former four-drug induction. CNS control could be obtained in most without cranial irradiation (CNS relapse-free survival >95%). The leukemic cell kill with a 24-h DNR infusion was equivalent to that of a 1-h infusion. DNR response was of less prognostic significance than prednisone response. The rapid rotation regimen failed to improve outcome as well as 6-TG in maintenance treatment. However, intensification of systemic treatment resulted in an increase in overall event-free survival (EFS) to approximately 80% which is comparable to other groups.

A classification based on T cell selection-related phenotypes identifies a subgroup of childhood T-ALL with favorable outcome in the COALL studies.

During T cell selection in the thymic cortex more than 90% of the thymocytes are eliminated by apoptosis. Based on this biology, we propose to define blasts of T cell acute lymphoblastic leukemia (ALL) with the phenotype of cortical thymocytes (CD1+ and/or CD4+ 8+) as selection-related (SR) and all other T-ALL immunophenotypes as non-selection-related (NSR). The COALL cooperative treatment studies for childhood ALL offer a tool to study the outcome in T-ALL subgroups as children with T-ALL are allocated uniformly to the high risk arm of the protocol. In the COALL-85, -89 and -92 protocols, 39/83 cases presented as SR and 44/83 cases as NSR. Five-year event-free survival of SR phenotype is significantly better compared to the NSR group (0.87 +/- 0.06 vs 0.66 +/- 0.07, log rank test, P = 0.01). T-ALL with SR phenotype is a distinct subgroup of leukemia with excellent prognosis under a high risk treatment protocol.

Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements.

To assess the clinical heterogeneity among patients with acute lymphoblastic leukemia (ALL) and various 11q23 abnormalities, we analyzed data on 497 infants, children and young adults treated between 1983 and 1995 by 11 cooperative groups and single institutions. The substantial sample size allowed separate analyses according to age younger or older than 12 months for the various cytogenetic subsets. Infants with t(4;11) ALL had an especially dismal prognosis when their disease was characterized by a poor early response to prednisone (P=0.0005 for overall comparison; 5-year event-free survival (EFS), 0 vs 23+/-+/-12% s.e. for those with good response), or age less than 3 months (P=0.0003, 5-year EFS, 5+/-+/-5% vs 23.4+/-+/-4% for those over 3 months). A poor prednisone response also appeared to confer a worse outcome for older children with t(4;11) ALL. Hematopoietic stem cell transplantation failed to improve outcome in either age group. Among patients with t(11;19) ALL, those with a T-lineage immunophenotype, who were all over 1 year of age, had a better outcome than patients over 1 year of age with B-lineage ALL (overall comparison, P=0.065; 5-year EFS, 88+/-+/-13 vs 46+/-14%). In the heterogeneous subgroup with del(11)(q23), National Cancer Institute-Rome risk criteria based on age and leukocyte count had prognostic significance (P=0.04 for overall comparison; 5-year EFS, 64+/-+/-8% (high risk) vs 83+/-+/-6% (standard risk)). This study illustrates the marked clinical heterogeneity among and within subgroups of infants or older children with ALL and specific 11q23 abnormalities, and identifies patients at particularly high risk of failure who may benefit from innovative therapy.