Are predictions of cancer response to targeted drugs, based on effects in unrelated tissues, the 'Black Swan' events?

Adverse effects of targeted drugs on normal tissues can predict the cancer response. Rash correlates with efficacy of erlotinib, cetuximab and gefitinib and onset of arterial hypertension with response to bevacizumab, sunitinib, axitinib and sorafenib, possible examples of 'Black Swan' events, unexpected scientific observations, as described by Karl Popper in 1935. The proposition is that our patients have individual intrinsic variants of cell growth control, important for tumor response and adverse effects on tumor-unrelated tissue. This means that the lack of predictive side effects in healthy tissue is linked with poor results of tumor therapy when tumor resistance is caused by mechanisms that protect all cells of that patient from the targeted drug effects.

[Regional distribution of physicians in Croatia]. / Regionalna raspodjela lijecnika u hrvatskoj.

The aim of this study was to show regional distribution of physicians in Croatia. Number of physicians members of the Croatian medical chamber and number of physicians in the system of mandatory health insurance were compared between the counties. In 2006 in Croatia there were 276 physicians per 100,000 inhabitants, i.e., 215 physicians per 100,000 inhabitants in the system of mandatory health insurance. The fewer number of physicians per 100,000 inhabitants in the system of mandatory health insurance, less then 150, were in Koprivnica-Krizevci County, Lika-Senj County and Vukovar-Srijem County, while the greatest number of physicians, more than 250 per 100,000 inhabitants, were in the City of Zagreb and Zagreb County, and Primorje-Gorski kotar County. There were significant differences in the number of physicians per 100,000 inhabitants between the counties (chi2 = 148.7, DF = 19, P < 0.001, chi2-test). Number of general practitioners (GPs) per 100,000 inhabitants in Croatia were 54.2, with range from 47.1 in Pozega-Slavonia County to 61.8 in Primorje-Gorski kotar County. Number of physician specialties in four basic specialties per 100,000 inhabitants in Croatian hospitals were for internal medicine 19.1, general surgery 11.0, gynecology and obstetrics 6.7 and pediatrics 7.8. There were significant differences in the number of physicians in four specialties (internal medicine, general surgery, gynecology and obstetrics and pediatrics) per 100,000 inhabitants between the counties (chi2 = 76.0, DF = 19, P < 0.001, chi2-test). Apart from the insufficient number of physicians in Croatia, an inadequate allocation of physicians in certain counties is also evident.

Radiofrequency ablation as locoregional therapy for unresectable hepatic malignancies: initial results in 24 patients with 5-years follow-up.

Radiofrequency ablation (RFA) is one treatment modality for unresectable liver metastases. Patients with hepatic malignancies (n = 24) underwent elective RFA. All tumors were ablated with a curative intent, with a margin of 1 cm, in a single session of RFA. The median diameter of tumor was 3.1 cm (range 1.7-6.9 cm). Studied patients were not candidates for resection due to multifocal hepatic disease, extrahepatic disease, proximity to major vascular structures or presence of cirrhosis with functional hepatic reserve inadequate to tolerate major hepatic resection. Complete tumor necrosis was achieved in 87.5% and tumor recurred in 3 patients (12.5%) with lesions larger than 5 cm. Distant intrahepatic recurrence was diagnosed in another 4 (16.7%). Distant metastases were found in 7 (29.2%) patients. Four of these 7 patients had also distant intrahepatic recurrence of disease. Two and 5-years survival rates were 41.7% (10 patients) and 8.3% (2 patients) respectively. RFA is safe and effective option for patients with unresectable hepatic malignancies smaller than 5 cm without distant metastatic disease. RF ablation resulted in complete tumor necrosis in 87.5% with 2 and 5-years survival rates much higher than with chemotherapy alone or only supportive therapy, when survival is measured in weeks or months. If RFA is unavailable, percutaneous ethanol injection therapy can be done but with inferior survival rates.

[Care of military and civilian casualties during the war in Croatia]. / Analiza zbrinjavanja vojnih i civilnih ranjenika u ratnoj agresiji na Republiku Hrvatsku.

AIM: The Yugoslav People's Army as aggressor on Croatia was well organized and equipped with weapons and medical supplies. On the other hand, the Republic of Croatia as a new country had no army of nor medical corps of its own. At the beginning of aggression we decided to establish an integrated civilian-military medicine system. This system started as a civilian organization, to develop along with the army structure. The aim of the study was to analyze the overall result of such organization all over the Croatian territory throughout war period. METHOD: Data on 30,520 wounded were collected from all military and civilian hospitals. The registration of information on all hospitalized wounded was established at the beginning of war. For this analysis, a questionnaire was structured consisting of 150 data per person. Data were entered in digital form and analyzed by surgeons and general medicine specialists. RESULTS: The wounded were hospitalized at 58 institutions, 43 of them civilian hospitals adjusted to military purposes. In total, there were 7 163 wounded civilians (23.5%) and 23,351 wounded soldiers. Only 613 (2%) soldiers were registered as members of enemy units, most of them treated as civilians because they had enough time to remove their uniforms. Among civilian casualties, there were 1132 (15.8%) children and 1 985 (27.7%) women. The wounds were inflicted by artillery (n = 9 652, 31.6%), small arms (n = 7 302, 23.9%) and mines (n = 4587, 15.0%). First aid was administred at frontline to 5065, 25.5% soldiers), at echelon II-IV to the majority of them, while there are no data on 10,644 wounded. Among the wounded, 61.1% were evacuated within one hour and 76.3% within two hours. On admission, 313 patients were unconscious, and 1913 somnolent or disoriented. Pneumothorax was present in 740, respiratory insufficiency in 1570, and pulmonary edema in 48 patients. Hemorrhage of varying grade was present in 11,967 and hemodynamic shock in 1802 patients. The most common injuries were those involving the muscles in 26,339 (37.7%), bones in 19,452 (27.9%), abdominal region in 4312 (6.2%), neural system in 3809 (5.5%), thoracic organs in 2443 (3.5%) and cardiovascular system in 2164 (3.1%) patients. Only very simple diagnostic procedures were used. Standard radiography was performed in 25403 (83,2%) and contrast medium examination in 790 (2.6%) patients. Very useful methods in traumatology like CT and US were only used in 1277 (84.2%) and 1103 (3.6%) patients, respectively, due to the lack of modern diagnostic equipment. In total, 25,745 (84.4%) patients were surgically treated. A total of 42,239 operations were performed including one per patient in 15,611 cases, two per patient in 6 184 cases, and three per patient in 23,380 cases. Hospital treatment resulted in recovery or improvement in 20,777 (79.8%) patients, whereas 334 patients were transferred to another hospital. Data were not recorded for 1688 patients. In total, good results were achieved in 81% of all treated cases. The mortality was 3.9% (n = 284) in hospitalized civilians and 1.95% (n = 395) in soldiers, yielding a mean mortality of 2.22%. The mortality of enemy soldiers was similar (2.85%). Taking into account 15 000 wounded persons treated on outpatient basis, total mortality was 1.49%. DISCUSSION: The high number of civilian casualties (23.5%) was the result of the aggressor's war strategy. They surrounded a number of civil settlements including large towns bombing them for months or even years. The enemy strategy is best illustrated by the number of wounded children and women. Unfortunately, the mortality in civilians (3.9%) exceeded that in soldiers (1.95%), for several reasons, primarily age, distance from surrounded villages and number of destroyed hospitals. The favorable aspect of the organization was cooperation of the first aid teams at the battle field and transportation organized by medical corps, and excellent definitive treatment at the adapted civilian hospitals to serve as military hospitals. The relatively good status on the admission was the result of good preparation for transport performed by high qualified doctors dislocated very close to the frontline. CONCLUSION: Despite the lack of diagnostic equipment and medical vehicles, and the availability of improvised military hospitals, good results were achieved in overall patient survival. The very high rate of success in hospital treatment and very low mortality rate were the result of excellent medical staff and integrated civilian-military medical service.