Chronologic annotation on the development of allergology and clinical immunology in Croatia

This issue of Acta Medica Croatica is dedicated to historical development and role of allergology and clinical immunology in Croatia. Also listed are the names of experts who have historically marked allergology and contributed to its development. Understanding the origin of allergies as immune phenomena occurred in Croatia simultaneously to many other European countries. The origin and development of institutions established in the early 1920s constituted the backbone of a solid vertical line, crucial for the development of allergology and immunology in Croatia during the past century. Interest of allergology experts from various medical specialties has resulted in the establishment of Allergy Section at the Croatian Medical Association in 1952, now Croatian Society of Allergology and Clinical Immunology of the Croatian Medical Association. It turned out that the work of institutions and physicians, as well as cooperation with the Croatian Immunological Society and other scientific institutions during the second half of the 20th century provided solid foundation for contemporary research, design and development of allergy subspecialty centers and units at various medical institutions all over Croatia. Members of the Croatian Society of Allergology and Clinical Immunology have played an important role in educating new generations of physicians and in the organization of numerous research projects, symposia, congresses and seminars. Continuous, scientific and professional work has resulted in active Society membership in the European Academy of Clinical Immunology and Allergology.     

Population-based study of genetic variation in individuals with autism spectrum disorders from Croatia

Background  

Genome-wide studies on autism spectrum disorders (ASDs) have mostly focused on large-scale population samples, but examination of rare variations in isolated populations may provide additional insights into the disease pathogenesis.     

Second-look laparotomy in epithelial ovarian carcinoma: Precise definition,sensitivity, and specificity of the operative procedure

Twenty-five women treated with chemotherapy for epithelial ovarian carcinoma underwent “second-look” laparotomy after thorough clinical and radiographic examinations failed to detect residual tumor. Chest roentgenogram, barium enema, upper gastrointestinal series with small-bowel follow through, and abdominopelvic CAT scan were obtained in all patients prior to operation. Inspection, palpation, and multiple biopsies were performed in accordance with precise and detailed protocol requirements. Eight patients (32%) had gross tumor found at laparotomy, while 6 (24%) had no suspicion of residual disease at operation but had cytologic or microscopic evidence of tumor found on review of submitted specimens. Eleven patients (44%) had no gross or microscopic evidence of residual ovarian carcinoma. After follow-up of from 4 to 25 months, 1 of these 11 patients (9%) has suffered a recurrence. The maximum sensitivity of “second-look” laparotomy is 85.7%, and the maximum specificity is 90.9% in this series. Any additional recurrences observed over time will decrease both the sensitivity and specificity of the operation. The sites of microscopic disease support rigid adherence to a precise operative procedure which should minimize the false negative rate.     

Quo vadetis coxibs?

After the withdrawall of rofecoxib from worldwide market, there is ongoing debate whether gastrointestinal safety of COX-2 inhibition compared to non-selective NSAID-s may come at the cost of increased cardiovascular events. In this paper the relevant data regarding mechanisms, effects and side effects of selected COX-2 inhibitors are presented. Possible class effect is disscused and proposed alternative therapies.     

Current osteoporosis treatment: reasons for adding vitamin D to alendronate

Recently, many studies showed need to administer vitamin D in treatment of osteoporosis. Vitamin D deficiency was proved in postmenopausal women with osteoporosis. Effects of vitamin D resulted in lower risk of fractures and falls, as well as improvement of neuromuscular performances. In more than ten years of practice and several short- and long-term clinical studies alendronate lowered the risk of vertebral and extravertebral fractures, improved BMD of all measured sites in postmenopausal women and men with osteoporosis. Positive results of alendronate were demonstrated in different entities like persons of various ages and grades of lower BMD or patients with glucocorticoid-induced osteoporosis. Combination of vitamin D with efficacious antiresorptive drug alendronate maintains all pharmacological features and proves clinical effects of lx weekly alendronate, partly eliminating need for vitamin D supplementation.     

Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial

Background

Chronic lymphocytic leukaemia (CLL) is an incurable and chronic disorder, with worsening prognosis for patients as their disease progresses. We compared the efficacy and safety of the combination of fludarabine and alemtuzumab with fludarabine monotherapy in previously treated patients with relapsed or refractory CLL.

Methods

Patients (aged ≥18 years) with CLL Binet stage A, B, or C or Rai stages I–IV were randomly assigned in a 1:1 ratio according to a computer-generated allocation schedule to open-label combination treatment (fludarabine 30 mg/m² per day and alemtuzumab 30 mg per day on days 1–3) or monotherapy (fludarabine 25 mg/m² on days 1–5) by use of an interactive voice response system. Both regimens were given intravenously for a maximum of six 28-day cycles. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00086580.

Findings

Fludarabine plus alemtuzumab (n=168) resulted in better PFS than did fludarabine monotherapy (n=167; median 23·7 months [95% CI 19·2–28·4] vs 16·5 months [12·5–21·2]; hazard ratio 0·61 [95% CI 0·47–0·80]; p=0·0003) and overall survival (median not reached vs 52·9 months [40·9–not reached]; 0·65 [0·45–0·94]; p=0·021) compared with fludarabine alone. All-cause adverse events occurred in 161 (98%) of 164 patients in the combination treatment group and 149 (90%) of 165 in the fludarabine alone group. Patients in the fludarabine plus alemtuzumab group had more cytomegalovirus events (23 [14%] vs one [<1%]) and grade 1 or 2 potentially alemtuzumab infusion-related adverse reactions (102 [62%] vs 22 [13%]). Grade 3 or 4 toxicities in the combination treatment and monotherapy groups were leucopenia (121 [74%] of 164 vs 55 [34%] of 164), lymphopenia (149 [94%] of 158 vs 53 [33%] of 161), neutropenia (93 [59%] of 157 vs 110 [68%] of 161), thrombocytopenia (18 [11%] of 164 vs 27 [17%] of 163), and anaemia (14 [9%] of 163 vs 28 [17%] of 164). The incidence of serious adverse events was higher in the combination treatment group (54 [33%] of 164 vs 41 [25%] of 165); deaths due to adverse events were similar between the two groups (ten [6%] vs 12 [7%]).

Interpretation

The combination of fludarabine and alemtuzumab is another treatment option for patients with previously treated CLL.

Funding

Genzyme.     

Total Tumour Mass Score (TTM): a New Parameter in Chronic Lymphocytic Leukaemia

S ummary . Total tumour mass score (TTM) is introduced as a new parameter in chronic lymphocytic leukaemia (CLL) in order to assess the tumour mass within all major body compartments. TTM is the sum of: (1) the square root of the number of peripheral blood lymphocytes per nl, (2) the diameter of the largest palpable lymph node in centimetres, and (3) the enlargement of the spleen below left costal margin in centimetres. The validity of the proposed scoring system was evaluated in a prognostic study on 256 CLL patients. Patients with high TTM (>9.0) at presentation had the expected median survival (EMS) of 39 months whereas patients with low TTM (<8.9) had EMS of 101 months ( P < 0.0005). TTM was a significant prognostic factor even when adjustment was performed for age, sex, lymphocyte count, response to therapy, TTM-distribution pattern and bone marrow failure. In contrast, the lymphocyte count was not prognostically significant when adjustment was performed for TTM. This suggests that TTM is a better indicator of tumour cell burden than the lymphocyte count. TTM measurement enables the analysis of the tumour mass size independently of other factors. TTM is a simple, objective parameter that can be measured as a continuous quantitative variable allowing derivation of new factors. TTM-doubling time and TTM-response to therapy were significant for prognosis ( P < 0.0005). The proposed scoring system can also be used for the study of the tumour mass distribution pattern.