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.

Identification of low-risk tumours in histological high-grade soft tissue sarcomas.

In more than one-third of patients with a histological high-grade malignant soft tissue sarcoma metastasis develops despite local control of the primary tumour. Hence, adjuvant chemotherapy is increasingly used for these relatively chemoresistant tumours which requires improved prognostication to exclude low-risk patients from overtreatment. We assessed the value of stepwise prognostication in a series of 434 histological high-grade STS of the extremity and trunk wall. Vascular invasion was used as the first discriminator whereafter the risk factors tumour necrosis, size (>8cm) and infiltrating growth pattern were used to discriminate high- and low-risk tumours. We identified a high-risk group with a cumulative incidence of metastasis >0.4 at 5 years, and a low-risk group, comprising half of the tumours, with a cumulative incidence of metastasis <0.15. The model was validated in an independent material of 175 patients. This model improved prognostication in STS and is of value for identifying patients who probably should not receive adjuvant chemotherapy.

Increased risk of malignancies in a population-based study of 818 soft-tissue sarcoma patients.

Soft-tissue sarcomas (STS) have been associated with various rare cancer syndromes and occur at increased frequencies in survivors of childhood cancer. Also adult patients with STS have been suggested to be at an increased risk of additional malignancies. After exclusion of syndrome-associated and radiation-induced sarcomas, we studied multiple primary malignancies in a population-based cohort of 818 patients with primary STS of the extremities and the trunk wall. In total, 203 other malignancies developed in 164 (20%) patients median 10 (0-32) years before and median 4 (0-35) years after the sarcoma diagnosis. Standardised morbidity ratios (SMRs) were determined for primary malignancies following a STS. Hereby individuals who had developed a STS were identified to be at increased risk of second primary malignancies (SMR for all malignant tumours=1.3; 95% CI=1.0-1.5; P=0.02) with STS being the only specific tumour type that occurred at an increased risk (SMR=17.6; 95% CI=8.1-33.5; P<0.001). Hence, this population-based series demonstrates a high frequency of second primary tumours among STS patients and indicates a particularly increased risk of developing a new STS.

Experiences from tissue microarray in soft tissue sarcomas.

The tissue microarray (TMA) technology was introduced in 1998 as a tissue preserving, high-throughput technique that allows studies of multiple markers in large sample sets. TMA slides can be analyzed using techniques such as immunohistochemistry and in situ hybridization and represents a powerful tool for the investigation of potential diagnostic and prognostic markers identified in DNA microarray studies. We review the TMA method, its reproducibility, advantages, limitations and future perspectives with specific focus on soft tissue sarcomas.

Tissue microarray technique in soft tissue sarcoma: immunohistochemical Ki-67 expression in malignant fibrous histiocytoma.

Malignant fibrous histiocytoma (MFH) represents a heterogeneous soft tissue sarcoma entity. The authors compared different methods to determine immunohistochemical staining in whole tissue sections, evaluated the tissue microarray technique, and assessed immunohistochemical heterogeneity using the proliferation marker Ki-67 in 47 histopathologic tumor blocks from 11 MFHs. Whole tissue sections were assessed counting 400 cells along a line and counting all cells in 10 high-power fields (0.16 mm2) with mean Ki-67 expression levels of 13% and 11%, respectively. For the tissue microarray technique, two to three 0.6-mm diameter biopsies were studied from each of the 47 tumor blocks. Good correlation was obtained between whole tissue immunohistochemistry and tissue microarray with the microarray method, giving on average 8.6% greater Ki-67 expression levels than the reference method. Immunohistochemical tumor heterogeneity, evaluated using the high-power field method, showed a median standard deviation of 2.3% within the tumor blocks and 2.5% between the blocks from the same tumor. The authors concluded that the tissue microarray technique yields good quality staining and expression levels for Ki-67 comparable with whole tissue methods in MFH, but because of tumor heterogeneity, several tumor blocks ideally should be studied and, because of loss of material in the microarray process, multiple biopsies should be taken. The feasibility of tissue microarray for immunohistochemical studies of soft tissue sarcomas offers new possibilities to study multiple markers in large tumor materials.

Radiation effects on S-phase duration, labelling index, potential doubling time and DNA distribution in head and neck cancer xenografts.

The effect of irradiation on S-phase duration (Ts), labelling index (LI), potential doubling time (Tpot), and cell cycle phase distributions was determined by DNA flow cytometry in xenografted human squamous cell carcinoma of the head and neck (SCCHN). Tumours were treated with a single dose of 3 Gy, and excised at intervals over a 90-h period. Six hours before each excision the tumours were labelled in vivo with bromodeoxyuridine (BrdUrd). Although the growth rate of irradiated tumours was comparable with that of untreated controls, analysis of BrdUrd uptake revealed a transient reduction of LI and a prolongation of Ts in irradiated tumours. Maximum mean Tpot was 931 days in irradiated tumours as compared to 13 days in untreated controls. The variations in Ts, LI and Tpot all occurred within the first hours after irradiation; during the remainder of the observation time, the values of the variables did not differ from those of untreated controls. In irradiated tumours the distribution of cells according to DNA content changed significantly on three occasions during the observation period: 1) Parallel to the initial lowering of LI and prolongation of Ts there was a transient increase in the proportion of cells in G0/G1 and a decrease in the proportion of cells in S and G2; 2) At 18 h, the most pronounced cell cycle phase redistribution occurred when the G0/G1 fraction decreased and the S and G2 phase fractions increased; 3) At 66 h (i.e., approximately one cell cycle later), the pattern was the same as that after 18 h. The findings suggest that the transient prolongation of DNA replication seen in SCCHN cells immediately after a single radiation dose is a symptom of DNA damage inflicted during late G1 or early S-phase, and that this disturbance in DNA synthesis is associated with the subsequent accumulation of cells in G2 phase.

Analysis of immunoglobulin isotype levels in acute pneumococcal bacteremia and in convalescence.

In 48 patients with a history of a pneumococcal bacteremia, serum taken during the acute phase of the infection was analyzed for IgG and IgG subclasses. Once the patients were free of infection, a serum sample was analyzed for IgG, IgG subclasses, IgA and IgM. In an additional 20 patients, it was only possible to analyze serum from the infection-free phase. Seventeen of 48 (35%) patients had reduced levels of total IgG or of one or more of the IgG subclasses during acute disease. Of the 48 patients in whom both acute phase and infection-free phase serum were analyzed, values of IgG (p < 0.001), IgG1 (p < 0.001), IgG2 (p < 0.001), IgG3 (p < 0.01) and IgG4 (p < 0.01) were decreased during the acute infection. During the infection-free phase, 12 of 68 (18%) patients had a recognizable immunodeficiency, including two patients with common variable immunodeficiency. Routine screening for immunoglobulins during the infection-free period could result in the discovery of previously unrecognized immunoglobulin deficiencies in patients with a history of bacteremic pneumococcal infection.