Hans Brincker

Sarcoid reactions in malignant tumours

Tumour-related tissue reactions resulting in the formation of epithelioid-cell granulomas have been known for almost 70 years. Such sarcoid reactions may occur in lymph-nodes draining an area housing a malignant tumour, in the tumour itself, and even in non-regional tissues. Overall, sarcoid reactions occur in 4.4% of carcinomas, in 13.8% of patients with Hodgkins disease, and in 7.3% of cases of non-Hodgkin lymphomas. Similar histologic changes in sarcoma appear to be extremely rare. Most probably, sarcoid reactions are caused by antigenic factors derived from the tumour cells, eliciting an immunological hypersensitivity reaction leading to the formation of epithelioid-cell granulomas. Sarcoid reactions may be a marker of an immunologically mediated antitumour response of macrophages activated by T-lymphocytes, and in Hodgkins disease there is evidence that patients with sarcoid reactions have a better prognosis. On occasion sarcoid reactions may be so extensive that they complicate the diagnosis of an underlying malignant disease. Problems may also arise of distinguishing between tumour-related sarcoid reactions and true systemic sarcoidosis.

The rise in incidence of lymphomas in Europe 1985–1992

A collaborative study was carried out of the descriptive epidemiology of the lymphomas from seven countries across Europe in the period 1985-1992. Careful attention was paid to sources of information and the data quality in close collaboration with expert histopathologists. The data were classified as non-Hodgkins lymphoma (NHL) and Hodgkins disease (HD). An attempt was made to put the data into a modified version of the Revised European American Lymphoma (REAL) classification. We observed an overall rise in total NHL throughout the time period in all European countries but no such trend in HD. The increase in NHL overall being 4.2% per annum, representing an increase of 4.8% in males and 3.4% in females per annum, was only marked in middle and old age. Such increases were observed in all participating areas except in Burgundy. Different countries, however, have different base rates, the rates being highest in Scandinavia and the Netherlands. The analysis by subcategory classification suggested that the increase in NHL was confined to the follicle centre cell type, extranodal B-cell, nodal T-cell and nodal lymphomas not otherwise specified, categories. These new observations present a picture of real increase in case incidence with no obvious explanation. The increases in NHL do not appear to be due solely to better diagnoses. Pending other explanations or refutation, these present a compelling picture of an inexorable rise in incidence of this disease.

Clinicopathological features and prognostic factors in extranodal non-Hodgkin lymphomas

Abstract In a Danish population-based non-Hodgkin lymphoma (NHL) registry, 1257 newly diagnosed NHL cases were registered over a 5-year period. Of these, 463 (37%) were extranodal. The gastrointestinal tract was the most common site of extranodal involvement (30% of the cases). Histologically, 44% of all extranodal NHL cases had high-grade, 17% intermediate and 27% low-grade features, while 12% were unclassified. The most common histological subtype (Kiel) was the centroblastic diffuse (23% of cases). 50% of all extranodal NHL were localised (stage I E or II E ) and 27% had B symptoms. Site-specific features included a strong age-correlation for thyroid and testes lymphoma (>50 years) and a high prevalence of female cases in thyroid and salivary glands lymphomas (M/F 0.14 and 0.30, respectively). Overall 7-year survival for extranodal NHL was 46% (median 4.9 years). Poor prognosis patients could be identified by the presence of one or more of the following presentation characteristics: age >65 years, B symptoms, high-grade histology, disseminated disease, elevated s-IgA and hyperuricaemia. Relative risk values ranged from 2.1 for age and B symptoms to 1.7 for hyperuricaemia.

Failure of oral pamidronate to reduce skeletal morbidity in multiple myeloma: a double‐blind placebo‐controlled trial

In order to study whether oral bisphosphonate therapy might prevent or reduce skeletal‐related morbidity in patients with newly diagnosed multiple myeloma who required chemotherapy, 300 patients were included in a randomized multi‐centre trial. Patients were given oral pamidronate at a dose of 300 mg daily, or placebo, in addition to conventional intermittent melphalan/prednisolone (and in some cases alpha‐interferon) treatment. With a median treatment duration of about 550 d, no statisticallly significant reduction in skeletal‐related morbidity (defined as bone fracture, related surgery, vertebral collapse, or increase in number and/or size of bone lesions) could be demonstrated. Pamidronate treatment also did not have any influence on patient survival or on the frequency of hypercalcaemia. However, in patients treated with pamidronate there were fewer episodes of severe pain (P = 0.02) and a decreased reduction of body height of 1.5 cm (P = 0.02). The overall negative result of the study is attributed to the very low absorption of orally administered bisphosphonates in general.

Fifty-five patient years' experience with a totally implanted system for intravenous chemotherapy

A subcutaneously implanted injection system represents a new method of central venous access. Seventy‐eight injection capsules were implanted in 75 cancer patients undergoing intermittent chemotherapy. The actuarial median functional survival of the injection capsules was 16 months, and with a cumulative function time of 55 patient years the complication rate was only one complication every 990 days. No cases of septicemia and few cases of local infection or clotting of the system were seen. Patient activities were not restricted, and maintenance of the system between treatment courses was unnecessary. However, in 9% of the implants a tendency to erosion through the skin was observed, necessitating explanation or reimplantation. Injection capsules seem to be particularly suited for intermittent chemotherapy, including short‐term infusions and blood sampling.

Long-term oral pamidronate treatment inhibits osteoclastic bone resorption and bone turnover without affecting osteoblastic function in multiple myeloma

Abstract: This study was performed as a cross‐sectional substudy to the Danish–Swedish Pamidronate Study, a randomized placebo‐controlled multicentre trial in multiple myeloma. The purpose was to evaluate the biological effects of long‐term treatment with oral pamidronate 300 mg daily on bone metabolism by using histomorphometry and analysis of cytokines and biochemical markers of bone turnover. Sixteen patients were included after median 27.5 months of protocolized treatment; 10 patients received active treatment and 6 patients placebo. When compared with placebo, pamidronate treatment was associated with: (a) marked decreased osteoclastic resorption rate (0.86±0.59 μm/d vs. 5.7±5.0 μm/d, p=0.002), and diminished activation frequency (0.20±0.18 yr−1 vs. 0.72±0.55 yr−1, p=0.014); (b) compensatory reduced volume referent bone formation rate (0.17±0.21 yr−1 vs. 0.71±0.54 yr−1, p=0.007), but unaltered mineral appositional rate; (c) neutral (–0.66±5.6 mm) vs. negative (–2.15±2.2 μm, p=0.013) bone balance per remodelling cycle; (d) higher trabecular bone volume (21.0±6.2% vs. 13.0±3.7%, p=0.01); (e) suppressed urinary excretion and serum levels of some of the biochemical markers of bone metabolism; and (f) significant reduction of circulating soluble interleukin‐6 receptor (IL‐6sR) (25.9±4.1 ng/ml vs. 32.1±6.6 ng/ml, p=0.04), and (g) a uniform tendency of lower serum and marrow plasma levels of IL‐6, IL‐1β, and TNFα. Thus oral pamidronate was absorbed in biologically active amounts, and reduced overall bone resorption and bone turnover without impairing osteoblastic bone formation. The observation that cytokine and cytokine receptor levels were reduced extends the possible and potential beneficial actions of bisphosphonates in multiple myeloma.

The influence of chemotherapy on survival after recurrence in breast cancer-a population-based study of patients treated in the 1950s, 1960s and 1970s

In a population-based study survival after recurrence was compared in three cohorts of patients with a primary diagnosis of breast cancer in 1959, 1969 and 1979, respectively. The use of chemotherapy after recurrence in these cohorts was either none, sporadic or widespread. This allowed a retrospective analysis of the survival impact of chemotherapy. Given the basic assumption that the natural history of breast cancer and the influence of endocrine therapy have not changed significantly during the 20-year period covered by the study, our data suggest that chemotherapy in recurrent breast cancer prolongs survival by 9.5 months in patients who survive more than 2 weeks from the start of treatment for this recurrence.

Direct intratumoral chemotherapy

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Immunohistologic separation of B-cell-positive granulomas from B-cell-negative granulomas in paraffin-embedded tissues with special reference to tumor-related sarcoid reactions

Frozen and formalin‐fixed paraffin‐embedded tissue sections were studied concurrently in 17 cases of granulomatous lesions of different etiologies using antibodies recognizing either fixation‐sensitive or fixation‐resistant antigens. In fixed tissues, the antibodies 4KB5 and L26 for B cells and UCHL1 and MT1 for T cells gave results similar to those obtained in frozen tissues with anti‐leu‐12/leu‐14 for B cells and T‐3 for T cells. Paraffin‐embedded sections from 35 additional cases of granulomatous lesions were studied retrospectively using the same markers. The combined results from all 52 cases show that granulomas can be divided into two main “families” according to the presence or absence of B cells within the granulomas: one is a B‐cell‐negative family of lesions to which sarcoidosis and mycobacterial infection belong; the other is a B‐cell‐positive family of lesions to which toxoplasmosis, granulomatous lesions of unknown significance and tumor‐related sarcoid reactions belong.

Adjuvant chemotherapy with cyclophosphamide or CMF in premenopausal women with stage II breast cancer

SummaryAfter total mastectomy and partial axillary dissection, 805 premenopausal women with stage II breast cancer were randomized to receive postoperative radiotherapy (RT) alone, RT + cyclophosphamide (C) for 12 monthly cycles, or RT + cyclophosphamide/methotrexate/5-fluorouracil (CMF) for 12 monthly cycles. At 3 years actuarial relapse-free survival for RT + C and RT + CMF was significantly better than for RT alone (p = 0.0009 and 0.0001, respectively). There was no significant difference in relapse-free survival between RT + C and RT + CMF.C resulted in more pronounced haematologic toxicity and a higher frequency of amenorrhoea and of alopecia than CMF, while CMF resulted in more pronounced nausea and stomatitis than C.In the preliminary results, C alone may be as effective as CMF in prolonging relapse-free survival in premenopausal women with stage II breast cancer.