Re-irradiation in Paediatric Tumours of the Central Nervous System: National Guidelines from the Swedish Workgroup of Paediatric Radiotherapy.

There is a lack of clinical protocols for re-irradiation in paediatric central nervous system (CNS) tumours. To fill this void, the Swedish Workgroup of Paediatric Radiotherapy (SBRTG) compiled national guidelines on re-irradiation in paediatric CNS tumours (diffuse intrinsic pontine glioma, ependymoma, germinoma and medulloblastoma). These have been in clinical practice since 2019 in all paediatric radiotherapy centres in Sweden. Since the implementation, the guidelines have been complemented with a yearly review on clinical outcome and toxicities in all paediatric patients treated according to the guidelines. This article presents the Swedish national guidelines on re-irradiation in paediatric CNS tumours.

Cladribine for untreated or early low-grade non-Hodgkin's lymphoma.

PATIENTS AND METHODS: Forty-four patients, with low-grade non-Hodgkin's lymphoma (LG-NHL) were included in a phase II study between June 1993 and May 1995 and treated with cladribine (CdA) 0.12 mg/kg as a 2 h i.v. infusion daily x 5, repeated after 28 days for up to 6 courses. Thirty-four patients were previously untreated and 10 had progressive disease after initial response to limited chlorambucil treatment. Five patients had also received involved field radiotherapy. Eight patients had mantle cell lymphomas, 22 follicle centre lymphomas, 5 lymphoplasmacytoid lymphomas, 4 small cell lymphocytic lymphomas, 4 marginal zone B-cell lymphomas and I had unclassified low-grade NHL. The response rate was 64%, with 11 (25%) CR and 17 (39%) PR while 5 (11%) patients progressed during treatment. The response rate was similar in previously treated and untreated patients. The median number of CdA courses delivered was 3 (1-6) in non-responding patients and 6 (2-6) in responders. Median survival from inclusion was not reached with a median follow-up of 40 months. The median time to progression was 7 mo for all patients, 25+ mo for CR and 16 mo for PR patients. Toxicity was sometimes severe with 2 treatment related deaths, one infectious related and one due to a mucocutaneous syndrome and pulmonary microembolism. In addition, 5 grade 3 or 4 infectious episodes were seen. Seven patients experienced grade 3 or 4 thrombocytopenia and 20 had grade 3 or 4 neutropenia. We conclude that the majority of patients with low-grade non-Hodgkin's lymphoma respond to CdA but that the adverse effects may be severe.

Maternal and perinatal risk factors for childhood brain tumors (Sweden).

Childhood brain tumors (CBT) include a diversity of rare neoplasms of largely unknown etiology. To assess possible maternal and perinatal risk factors for CBT according to subtype, we carried out a nested (within Swedish birth-cohorts, 1973-89) case-control study, utilizing data from the nationwide Birth Registry. We ascertained incident brain tumor cases through linkage of the nationwide Birth and Cancer Registries and randomly selected five living controls from the former, matching each case on gender and birthdate. There were 570 CBT cases, including 205 low grade astrocytomas, 58 high grade astrocytomas, 93 medulloblastomas, 54 ependymomas, and 160 'others.' Risks for all brain tumors combined were elevated in relation to: (i) three maternal exposures-oral contraceptives prior to conception (odds ratios [OR] = 1.6, 95 percent confidence interval [CI] = 1.0-2.8), use of narcotics (OR = 1.3, CI = 1.0-1.6), or penthrane (OR = 1.5, CI = 1.1-2.0) during delivery); (ii) characteristics of neonatal distress (a combined variable including low one-minute Apgar score, asphyxia [OR = 1.5, CI = 1.1-2.0]) or treatments for neonatal distress (use of supplemental oxygen, ventilated on mask, use of incubator, scalp vein infusion, feeding with a jejunal tube [OR = 1.6, CI = 0.9-2.6]); and (iii) neonatal infections (OR = 2.4, CI = 1.5-4.0). Higher subtype-specific risks, observed for a few risk factors, did not differ significantly from the risk estimates for all subtypes combined for the corresponding risk factors. Childhood brain tumors were not associated significantly with other maternal reproductive, lifestyle, or disease factors; perinatal pain, anesthetic medications, birth-related complications; or with birthweight, birth defects, or early neonatal diseases. These findings suggest several new leads, but only weak evidence of brain tumor subtype-specific differences.

Lymphoma incidence in a Swedish county during 1969-1987.

The incidence of lymphoid malignancies (acute leukemias and myelomatosis excluded) during 1969-1987 in the County of Uppsala was calculated on the basis of the regional cancer register and local registers from the only oncological, hematological, dermatological and pathological departments in this well-defined geographical area. Of the 774 patients included, 639 had histopathological specimens available, all of which were re-examined. Seventy-nine patients were diagnosed on the basis of bone marrow investigations (greater than 70% re-examined, all had a low-grade non-Hodgkin's lymphoma = NHL) and 54 on fine-needle aspiration biopsies (not re-examined). Seventy-nine of the lymphoma diagnoses were based on autopsy specimens. The overall age standardized incidence was 16.2/100,000/year (NHL: 13.6, Hodgkin's disease = HD: 1.5) according to the Swedish 1970 census (according to world standard population: 10.2); male: 20.9 (12.9) and female: 12.4 (7.9). The annual change in trend was +3.0% +/- 2.6 (NHL: +3.6% +/- 2.4, HD: no change). The omission of the 54 'fine needle cases' led to an overall incidence of 15.0 (9.7) and an annual change in trend of +3.5% +/- 1.9. Among the histopathological specimens, an NHL was found in 524 patients and HD in 69. In 46 registered patients, the diagnosis malignant lymphoma was wrong. The diagnosis changed to NHL in 43 patients registered as HD.

Tumor markers in malignant lymphomas and myeloma.

Malignant lymphomas--divided into Hodgkin's disease (HD) and non-Hodgkin lymphomas (NHL)--comprise a heterogeneous group of disorders. The normal counterparts of NHL tumour cells are various cells in the lymphocyte differentiation chain. The origin of Hodgkin and Reed-Sternberg cells is not elucidated, but it is today thought to possibly be a lymphoid cell. Myeloma stands morphologically close to NHL in that the tumour cell is a B lymphoid cell--sometimes there is a floating border between myeloma/plasmacytoma and immunocytoma (Kiel classification). The three entities have most serum markers in common, although to some extent of different usefulness for different entities. In this group of tumours, the main role of serum markers is not to act as a diagnostic tool, but to provide prognostic information and facilitate the detection of early relapses. In low grade NHL, serum markers can in addition aid in the decision on when to initiate therapy. New-comers in the serum marker business are the cytokines, some of which can now be detected in serum.

Myelosarcoma without acute leukaemia: immunohistochemical and clinico-pathologic characterization of eight cases.

Eight cases of myelosarcoma without acute leukaemia at time of diagnosis were reviewed and biopsies were immunostained using antibodies reacting with myeloid/monocytic markers. Initial tumour location included lymph nodes, paranasal sinuses, nasopharyngeal and/or orbital regions and other extranodal locations. Three cases developed acute myeloblastic leukaemia within 1-9 months. Diagnosis was correct in four of the cases, in the other cases a non-Hodgkin's lymphoma was initially diagnosed. Morphological examination showed a blastic but variable appearance of the tumours. In a few cases cytoplasmic granulation was present. Chloroacetate esterase was present in all cases. In paraffin sections cathepsin G. elastase or lysozyme were present in all cases except one. In frozen material from four of the cases, the myeloid markers CD 11c and CD 33 were present (all cases) and CD 13 and Ki M8 in 3/4 cases.

Immunophenotype analysis of B-CLL lymphoma and immunocytoma.

The differential diagnosis between lymphocytic lymphoma of the B-CLL type and immunocytoma (IC) can be difficult when it is based only upon morphological criteria. With the aim of improving the distinction between these subgroups, frozen sections of lymph nodes or other biopsied tissues from 14 cases of B-CLL and 16 cases of IC were investigated according to immunophenotype. A panel of 13 B cell-associated and 2 T cell-associated monoclonal antibodies was used. All but one of the B-CLL cases were FMC7-, while 14/16 IC cases were FMC7+ (p less than 0.001). The two negative IC cases were both of the lymphoplasmacytic type, claimed to be "more differentiated" than the lymphoplasmacytoid type. We suggest that the cells in these cases are mature enough to have lost their FMC7 positivity, similar to plasma cells. There was also a statistically significant (p less than 0.01) difference, although not as pronounced, for the anti-CD38 antibody (Leu-17, B-CLL: 3/14, IC: 10/16 positive). No significant difference in expression of determinants was found for any of the other antibodies.

Primarily asymptomatic low-grade non-Hodgkin lymphomas: prediction of symptom-free survival and total survival.

Low-grade non-Hodgkin lymphomas (NHL) constitute a group of tumours with an often long survival time but, at present, with little--or no--chance of cure if the disease is not strictly local. In primarily asymptomatic patients, treatment may either be started immediately after diagnosis or deferred until symptoms occur. The possibility of predicting the symptom-free time was investigated in 64 non-selected initially asymptomatic patients with advanced low grade NHL, all of whom had treatment deferred until symptoms occurred. The most powerful predictor was the histopathological subgroup. Lymphocytic (LC) and follicular centroblastic-centrocytic (fCBCC) lymphomas had a median symptom-free period of 2 years, which was four times longer than that for immunocytoma (IC) and follicular and diffuse CBCC (fdCBCC). In addition, the serum levels of deoxythymidine kinase (S-TK) and lactic dehydrogenase (S-LDH) could predict the symptom-free period. This did not apply to S-Haptoglobin, S-Orosomucoid or stage. In a multivariate analysis, only S-TK gave additional information to histopathology. The only variable that predicted the overall survival time was the length of the symptom-free period.

Prognostic relevance of serum-markers in relation to histopathology, stage and initial symptoms in advanced low-grade non-Hodgkin lymphomas.

The prognostic relevance of 4 different serum markers (deoxythymidine kinase = S-TK, lactic dehydrogenase = S-LDH, S-Haptoglobin and S-Orosomucoid) in relation to histopathology according to the Kiel classification, stage and presence or absence of initial symptoms were investigated in 168 consecutive cases of low-grade non-Hodgkin lymphomas (NHL). All serum markers, as well as the other three parameters, gave prognostic information. Univariate analysis yielded a high predictive value (p less than 0.0002) for both S-TK and S-LDH. The best information regarding the probability of survival was, however, obtained from the presence or absence of symptoms from lymphoma manifestations other than those caused by a strictly local tumor mass. Since S-TK and S-LDH correlated well with each other, only the better of them, S-TK, gave information additional to initial symptoms in a multivariate test.

Intracytoplasmic immunoglobulins in the differential diagnosis of lymphocytic lymphomas of the B-CLL type and immunocytic lymphomas.

One hundred and thirty-three consecutive cases originally classified either as a lymphocytic lymphoma of the B-CLL type or as an immunocytic (IC) lymphoma could be reclassified morphologically and analyzed for the presence of cytoplasmic immunoglobulins (cIg) with the PAP-technique. The morphologic reclassification confirmed the initial diagnosis in most cases, whereas after staining for cIg, the diagnosis was changed in a large number of cases, i.e. from B-CLL to IC, or the reverse, or from IC of the polymorphic subtype (ICp) to 'high-grade' non-Hodgkin lymphoma (NHL). Cases classified as IC were often localized (stage I+II: 22/43) with a long disease-free survival after local radiation therapy, while B-CLL were usually generalized. For patients in stage IV, the prognosis of B-CLL was significantly superior to that of IC, which in turn was superior to the prognosis of cases referred to as 'high-grade' NHL. The difficulties in the morphologic distinction between B-CLL and IC on one hand and between ICp and some 'high-grade' NHL on the other hand, as well as the clinical significance of these distinctions, are discussed.