Les White

A syndrome of thrombosis and hemorrhage complicating l-asparaginase therapy for childhood acute lymphoblastic leukemia**

L-Asparaginase therapy for childhood acute lymphoblastic leukemia causes deficiencies of plasma hemostatic proteins, especially antithrombin, plasminogen, and fibrinogen. Severe thromboses and hemorrhages occurred in 18 children receiving vincristine, prednisone, and asparaginase therapy for ALL. Thirteen children had intracranial thrombosis or hemorrhage, four had extremity thrombosis, and one had both an intracranial hemorrhage and an extremity thrombosis. These events occur characteristically in the third and fourth weeks of therapy during or just after a three-week course of L-asparaginase. Symptoms of headache, obtundation, hemiparesis, and seizure were common for the intracranial events: local pain, swelling, and discoloration were common for the extremity thromboses. These complications have been recognized in 1 to 2% of children undergoing induction therapy which includes asparaginase.

'It's an Interesting Conversation I'm Hearing': The Doctor as Manager

The aim of this article is to outline in discursive-linguistic terms how doctor-managers (or ‘physician-executives’ as they are termed in the USA) manage the incommensurate dimensions of their boundary position between profession and organization. In order to achieve this we undertook a discourse analytical study of both recorded, situated talk and open interview data focusing on one doctor-manager navigating between profession and organization. The doctor-manager at the centre of this study locates himself on the boundary of at least three discourses which, in many respects, are incommensurate. These are the profession-specific discourse of clinical medicine, the resource-efficiency and systematization discourse of management, and an interpersonalizing discourse devoted to hedging and mitigating contradictions. While this multi-vocality in itself is not surprising, data show that the doctor-manager positions himself across these discourses and manages their inherent incommensurabilities before a heterogeneous audience and on occasions even within the one utterance. In this particular case, boundary management is achieved by weaving incommensurable positions together into the social and linguistic dynamics of a single, heteroglossic stream of talk. This highly complex and dialogic strategy enables the doctor-manager to dissimulate the disjunction between his reluctance to impose organizational rules on his medical colleagues and his perception that such rules, in the future (to some extent at least), will be the appropriate means for managing the clinical work, and through that the organization.

The rhombotin gene family encode related LIM-domain proteins whose differing expression suggests multiple roles in mouse development☆

The rhombotin (RBTN1 or Ttg-1) gene was first identified at a chromosome translocation in a T-cell acute leukaemia and later used to isolate two related genes (RBTN2 or Ttg-2 and RBTN3). Complete characterization of these genes in man and mouse shows that all three encode cysteine-rich proteins with typical LIM domains. RBTN1 and RBTN3-derived proteins have 98% identity in the LIM domains but are located on separate chromosomes in man and in mouse while RBTN1 and RBTN2, both located on human chromosome 11p but are on separate chromosomes in mouse, are only 48% identical in this part of the protein. The exon organization of RBTN1 and RBTN3 genes are similar, both having an intron, absent from the RBTN2 gene, in the LIM2-encoding region. The remarkable similarity between rbtn-1 and rbtn-3 proteins is parallelled in their expression patterns in mouse development, since both genes show high expression in restricted areas of the brain, but little lymphoid expression. rbtn-2 expression, however, is more ubiquitous. This gene shows a low level of thymus expression but high expression in fetal liver, adult spleen and B-cell lines, consistent with a role in B-cell development. These results suggest multiple cellular targets for the action of these proteins during development.

A cluster of chromosome 11p13 translocations found via distinct D-D and D-D-J rearrangements of the human T cell receptor delta chain gene.

Human T cell tumours have few consistently occurring translocations which provide markers for this disease. The translocation t(11;14)(p13;q11), however, seems to be an exception, since it has been repeatedly observed in T‐ALL. We have analysed a number of T‐ALL samples carrying the t(11;14) with a view to assessing the nature of the translocated sequences on chromosomes 11 and 14. Three of the tumours studied have breakpoints, at 14q11, within the T cell receptor delta chain locus, while a fourth appears to break in the J alpha region. The TCR delta sequences involved in the translocation junctions are made from D delta‐D delta‐J delta joins or from D delta‐D delta joins, allowing us to define distinct human D delta and J delta segments. These results allow us to make a comparison between the human and mouse TCR delta loci, both as regards sequence and rearrangement hierarchies. The disparate translocation breakpoints at chromosome 14q11 contrast with the marked clustering of breaks at chromosome 11p13; in all four cases, the breakpoint occurs within a region of less than 0.8 kb of chromosome 11. The analysis of junctional sequences at the 11p13 breakpoint cluster region only shows a consensus heptamer‐like sequence in one out of four tumours analysed. Therefore, recombinase‐mediated sequence specific recognition is not the only cause of chromosomal translocation.

Chemotherapy in retinoblastoma: current status and future directions.

In the past, chemotherapy has had only a minor role in the treatment of retinoblastoma. There are three clinical settings in which chemotherapy may be useful, namely, in intraocular retinoblastoma, in cases of micrometastatic spread, and where there are overt extraocular metastases. Clinical trials in all three settings have been impeded by biological, statistical, and ethical limitations. Extensive review of the literature, including case reports, small retrospective series, and occasional prospective studies, does not lead to any clear conclusions. However, responsiveness of retinoblastoma to chemotherapy in each of the above categories has been documented, and cyclophosphamide is consistently the most effective single agent. For small intraocular tumors, there may be a role for a combination of nonoperative treatment modalities. Whether decreased occurrence of extraocular relapse is produced by the use of adjuvant chemotherapy for presumed micrometastatic disease remains controversial. A prospective randomized study of stratified high-risk categories of patients needs to be done on an international level. The most widely accepted regimen in this setting is the combination of cyclophosphamide and vincristine. Improving the survival of patients with overt metastases is a major challenge, which is especially relevant to the less developed parts of the world. Several multi-agent regimens, particularly in combination with bone marrow transplantation, offer some promise. Experimental models are being used to overcome some of the limitations of clinical studies. Evaluations of responsiveness to chemotherapy, both in cell culture and animal models, are being conducted. Other areas being investigated include pharmacologic enhancement of radiotherapy and hematoporphyrin photodynamic therapy, use of tumor cell targeting techniques, differentiating agents, vitamin D, and immunotherapy. The nude mouse intraocular xenograft model appears to confirm clinical observations for responsiveness to conventional therapeutic agents.

Postoperative Chemotherapy in Children Less Than 4 Years of Age with Malignant Brain Tumors: Promising Initial Response to a Vetopec-based Regimen A Study of the Australian and New Zealand Children's Cancer Study Group (anzccsg)

Purpose: Postoperative chemotherapy with indefinite postponement of radiation therapy in children <4 years old with brain tumors was investigated in a multi-institutional study. Patients and Methods: From 1991 to 1995. 42 patients aged 3 to 47 months (median 20) with brain tumors were enrolled in a 2-phase chemotherapy protocol: 16 patients had medulloblastoma (MB); 8 had supratentorial primitive neuroectodermal tumor (PNET); 14 had ependymoma; and 4 had other tumors. The initial phase was comprised of 4 courses of the 3-drug regimen: vineristine (VCR), etoposide (VP-16). and intensive cyclophosphamide (CPA) in a previously reported schedule (VFTOPEC). The continuation phase was comprised of 2-drug courses: A. CPA + VCR: B. cisplatin + VP-16; and C. carbopfatin + VP-16, for a total duration of 64 weeks. Results: Response to VETOPFC was evaluable in 28 patients with postresection residual (25) and/or metastatic (1 M2, 6 M3) tumor. There were 9 complete responses (CR) and 9 partial responses (PR) with a combined CR + PR of 64% (95% confidence interval [CI] 44 to 81). In 12 evaluable patients with MB, CR + PR was 82% (48 to 98); in 6 patients with PNET. 50% (12 to 88); and, in 8 patients with ependymoma. 86% (42 to 99). Of 40 patients eligible for further analysis, 6 remain progressionfree at a median of 30 months, 14 are alive at a median of 38 months. 29 have progressed at a median of 7 months (range. 2 to 37 months), and 26 have died. The progression-free and overall survival rates at 36 months are estimated to be 11% (95% CI 1 to 22) and 34% (18 to 50). respectively. Conclusions: The initial response to the VETOPEC regimen is encouraging and warrants study of further dose escalation. Survival remains poor with current strategies in this high-risk population.

Acute non-lymphocytic leukemia following multimodality therapy for retinoblastoma

The genetic form of retinoblastoma carries a high risk of secondary malignant neoplasm, apparently not related to the use of chemotherapy. A child with unilateral non‐genetic retinoblastoma who had received chemotherapy and radiation therapy and developed acute non‐lymphocytic leukemia (ANLL) is reported. The occurrence of ANLL and Retinoblastoma has not been previously reported.

Postoperative chemotherapy without radiation in young children with malignant non-astrocytic brain tumours. A report from the Australia and New Zealand Childhood Cancer Study Group (ANZCCSG).

Young children with malignant brain tumours have particularly poor survival and manifest severe sequelae of radiation therapy. A multi-institutional pilot study of post-operative primary chemotherapy for children under 3 years with primitive neuroectodermal tumours (PNET) or ependymoma was initiated in 1987. The chemotherapy protocol comprised earboplatin, vincristine and the “eight drugs in 1 day” regimen. Radiation was recommended only if tumour progression or recurrence was documented. A total of 14 patients between 5 and 36 months of age were enrolled. Seven had supratentorial tumours (PNET, pinealoblastoma, intracranial retinoblastoma) with multiple predictors of adverse outcome. Four of these responded to initial chemotherapy but subsequently progressed and all had died by 16 months from diagnosis. The seven patients with infratentorial tumours (three medulloblastomas, four ependymomas) had more favourable predictors of outcome: no meningeal dissemination and gross macroscopic resection in six of the seven cases. One patient progressed rapidly and died within 5 months. The other six are alive at 37–57 months from diagnosis. Four are in continuous complete remission at 57, 51, 41 and 37 months, respectively from the time of their tumour resection. One is described as having stable disease with a persistent radiographic lesion at 41 months from diagnosis. One has relapsed on two occasions and is the only surviving patient to have been irradiated. Intelligence scores for the six long-term survivors have thus for remained within the normal range. It is suggested that some infants with standard-risk ependymoma and, possibly, medulloblastoma may be cured without radiation therapy.

Chemotherapy for retinoblastoma : where do we go from here ? A review of published literature and meeting abstracts, including discussions during the Vth International Symposium on Retinoblastoma, October 1990

The history of the application of chemotherapy in the management of retinoblastoma (RB) may conveniently be divided into three eras: initial enthusiasm (from early 1950s to mid 1970s), realism (from late 1970s to mid 1980s) and possibility (from mid 1980s to the future). Available data from each of these eras are reviewed in the clinical categories of: intraocular RB, micrometastatic RB and overt dissemination. The latter is further sub-classified into: orbital invasion, central nervous system involvement and systemic metastases. Experimental models are described with particular emphasis on future directions. Early reports led to initial optimism subsequently dampened by a more critical approach. Recent results with increasingly effective chemotherapeutic regimens offer the possibility of a valid contribution in each of the above clinical settings. A multi-modality approach is recommended optimizing a combination of the most active drugs with continuing refinements of other techniques. In selected patients with intraocular, and particularly bilateral RB, visual outcome may be enhanced by the combined use of non-surgical modalities. Adjuvant treatment of presumed micrometastases needs to be studied within risk categories defined by prognostic factors. Invasion of the ocular coats and/or of the optic nerve are the most relevant factors but there are continued difficulties in defining the extent of involvement and eligibility criteria for such a strategy. Overt dissemination has recently been demonstrated to be curable in each of the three subgroups above. Intensive regimens incorporating cyclophosphamide, vincristine, cisplatinum, etoposide and possibly doxorubicin, plus intrathecal agents in combination with radiation therapy and, in some instances supplemented by bone marrow transplantation have produced promising results. Multi-institutional collaboration has been encouraged by the recently formed International Committee for the Staging and Management of Retinoblastoma, opening the way for prospective clinical trials. At the same time both laboratory and clinical experimental studies are being pursued and may produce further improvements in currently available strategies.

Dose-intensive cyclophosphamide with etoposide and vincristine for pediatric solid tumors: a phase I/II pilot study by the Australia and New Zealand Childhood Cancer Study Group.

PURPOSE This pilot study of the Australia and New Zealand Childhood Cancer Study Group investigated the effectiveness and toxicity of a regimen incorporating vincristine (VCR), etoposide, and divided-dose, escalating cyclophosphamide (CPA) (VETOPEC) in 23 patients aged 1 to 20 years with solid tumors. PATIENTS AND METHODS Seventeen patients (group A) had recurrent or refractory tumors after prior multiagent therapy, and six patients (group B) with adverse prognostic indicators were treated at initial presentation. Treatment cycles were 21 to 28 days and consisted of vincristine (0.05 mg/kg) on days 1 and 14, with etoposide (2.5 mg/kg/d) plus escalating CPA on days 1, 2, and 3. The CPA dosage was escalated from 30 mg/kg/d in cycle no. 1 by 5 mg/kg/d in each cycle to a maximum of 55 mg/kg/d in cycle no. 6. RESULTS Of 20 patients assessable for tumor response, 19 (95%) responded after two to six cycles of VETOPEC: seven complete responses (CRs); eight very good partial responses (VGPRs); and four partial responses (PRs). In group A, 13 of 14 (93%) assessable patients responded (five CRs, four VGPRs, four PRs), and in group B, five stage IV and one stage III patient achieved two CRs and four VGPRs. The principal toxicity was myelosuppression. Grade IV neutropenia occurred after 98% of cycles, and the incidence of grade IV thrombocytopenia increased from 37% after cycle no. 1 to 91% after cycle no. 6 (P = .002). A total of 115 cycles delivered were followed by 62 febrile admissions (54%), and showed a significant rise with increasing cycles (P = .001). One patient died of septicemia. CONCLUSION This combination and scheduling produced a high response rate in patients with recurrent, refractory, or advanced solid tumors of childhood. Further studies of this regimen and of strategies to reduce hematologic toxicity are warranted.