Izražajnost proteina HER-2 i njegova prognostička vrijednost u karcinomu dojke

Immunohistochemical analysis of the HER-2 protein expression in ductal invasive breast cancer was done on archival paraffin-embedded breast cancer tissue using specific monoclonal antibodies. All of the 190 analyzed patients were treated at the University Hospital for Tumors, Zagreb, Croatia, from September 2002 to September 2003. Year of birth, tumor size, histological type of tumor, histological grade, lymph-node status, steroid receptors, HER-2 expression, nuclear grade and vascular invasion were determined for each patient. HER-2 overexpression was found in 24% of the patients. HER-2 overexpression was not associated with age, but it was associated significantly with tumor size, worse histological and nuclear grades, lack of steroid receptors, lymph node involvement and positive vascular invasion. Steroid receptors expression was associated significantly with better nuclear grade and negative vascular invasion.Izražajnost HER-2 proteina te steroidnih receptora u duktalnom invazivnom karcinomu dojke određena je imunohistokemijski, uporabom monoklonskih protutijela. Korišten je arhivski bioptički materijal uklopljen u parafinske blokove. Svih 190 analiziranih bolesnica liječeno je u Klinici za tumore, Zagreb, Hrvatska, u razdoblju od rujna 2002. do rujna 2003. godine. Svakoj bolesnici utvrđena je godina rođenja, veličina tumora, histološka slika tumora, histološki gradus tumora, zahvaćenost pazušnih limfnih čvorova metastazama, nalaz steroidnih receptora, nalaz HER-2 proteina, nuklearni gradus te vaskularna invazija. Analizom imunohistokemijskih rezultata utvrđena je izražajnost HER-2 proteina kod 24% bolesnica. Nije utvrđena statistički značajna razlika u izražajnosti HER-2 proteina s obzirom na dob bolesnica, a utvrđena je povezanost HER-2 proteina s nepovoljnijim prognostičkim čimbenicima: većom veličinom tumora, nepovoljnijim stupnjem diferenciranosti tumora, većom zahvaćenosti pazušnih limfnih čvorova metastazama, negativnim nalazom steroidnih receptora, pozitivnom vaskularnom invazijom te nepovoljnijim nuklearnim gradusom. Statistički je utvrđena i povezanost steroidnih receptora s povoljnijim prognostičkim čimbenicima: povoljnijim nuklearnim gradusom i negativnom vaskularnom invazijom

Biomarkers of aging associated with past treatments in breast cancer survivors.

Radiation and chemotherapy are effective treatments for cancer, but are also toxic to healthy cells. Little is known about whether prior exposure to these treatments is related to markers of cellular aging years later in breast cancer survivors. We examined whether past exposure to chemotherapy and/or radiation treatment was associated with DNA damage, telomerase activity, and telomere length 3-6 years after completion of primary treatments in breast cancer survivors (stage 0-IIIA breast cancer at diagnosis). We also examined the relationship of these cellular aging markers with plasma levels of Interleukin (IL)-6, soluble TNF-receptor-II (sTNF-RII), and C-reactive protein (CRP). Ninety-four women (36.4-69.5 years; 80% white) were evaluated. Analyses adjusting for age, race, BMI, and years from last treatment found that women who had prior exposure to chemotherapy and/or radiation compared to women who had previously received surgery alone were more likely to have higher levels of DNA damage (P = .02) and lower telomerase activity (P = .02), but did not have differences in telomere length. More DNA damage and lower telomerase were each associated with higher levels of sTNF-RII (P's < .05). We found that exposure to chemotherapy and/or radiation 3-6 years prior was associated with markers of cellular aging, including higher DNA damage and lower telomerase activity, in post-treatment breast cancer survivors. Furthermore, these measures were associated with elevated inflammatory activation, as indexed by sTNF-RII. Given that these differences were observed many years after the treatment, the findings suggest a long lasting effect of chemotherapy and/or radiation exposure

Products of Vitamin D3 or 7-Dehydrocholesterol Metabolism by Cytochrome P450scc Show Anti-Leukemia Effects, Having Low or Absent Calcemic Activity

BACKGROUND. Cytochrome P450scc metabolizes vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,23(OH)2D3, as well as 1-hydroxyvitamin D3 to 1a,20-dihydroxyvitamin D3 (1,20(OH)2D3). It also cleaves the side chain of 7-dehydrocholesterol producing 7-dehydropregnenolone (7DHP), which can be transformed to 20(OH)7DHP. UVB induces transformation of the steroidal 5,7-dienes to pregnacalciferol (pD) and a lumisterol-like compounds (pL). METHODS AND FINDINGS. To define the biological significance of these P450scc-initiated pathways, we tested the effects of their 5,7-diene precursors and secosteroidal products on leukemia cell differentiation and proliferation in comparison to 1a,25-dihydroxyvitamin D3 (1,25(OH)2D3). These secosteroids inhibited proliferation and induced erythroid differentiation of K562 human chronic myeloid and MEL mouse leukemia cells with 20(OH)D3 and 20,23(OH)2D3 being either equipotent or slightly less potent than 1,25(OH)2D3, while 1,20(OH)2D3, pD and pL compounds were slightly or moderately less potent. The compounds also inhibited proliferation and induced monocytic differentiation of HL-60 promyelocytic and U937 promonocytic human leukemia cells. Among them 1,25(OH)2D3 was the most potent, 20(OH)D3, 20,23(OH)2D3 and 1,20(OH)2D3 were less active, and pD and pL compounds were the least potent. Since it had been previously proven that secosteroids without the side chain (pD) have no effect on systemic calcium levels we performed additional testing in rats and found that 20(OH)D3 had no calcemic activity at concentration as high as 1 µg/kg, whereas, 1,20(OH)2D3 was slightly to moderately calcemic and 1,25(OH)2D3 had strong calcemic activity. CONCLUSIONS. We identified novel secosteroids that are excellent candidates for anti-leukemia therapy with 20(OH)D3 deserving special attention because of its relatively high potency and lack of calcemic activity.National Institutes of Health (R01A052190

Sustavno antineoplastično liječenje metastatskog raka dojke

Systemic therapy of metastatic breast cancer is not curative and its goal is life prolongation and improvement of quality of life. Treatment of metastatic breast cancer usually involvesendocrine therapy and/or chemotherapy with or without targeted therapy. The use of the minimally toxic endocrine therapies is preff ered to the use of cytotoxic therapy whenever reasonable.Sustavno liječenje metastatskog raka dojke nije kurativno već se provodi u svrhu produženja života i poboljšanja kvalitete života. Sustavno liječenje se sastoji od endokrine terapije i/ili kemoterapije uz ili bez primjene ciljane biološke terapije. U liječenju metastatskog raka dojke preferirani oblici liječenja su oni najmanje toksični te se endokrina terapija primjenjuje kad god je to moguće

Sustavno antineoplastično liječenje raka dojke

Breast cancer is the most common cancer in women. Early breast cancer is potentially curable disease. Systemic adjuvant therapy is created to treat micrometastatic disease or destroy breast cancer cells that have spread from the breast and regional lymph nodes, but have not yet formed visible distant metastases. Systemic adjuvant therapy is based on chemotherapy with or without targeted therapy, and endocrine therapy, sometimes in combination with adjuvant irradiation, usually is conducted after surgery. The aim of adjuvant therapy is to decrease recurrence rate and extension of overall survivalRak dojke najčešća je zloćudna bolest u žena, potencijalno izlječiva u ranom stadiju. Sustavno adjuvantno liječenje osmišljeno je za uništenje mogućih mikrometastaza proširenih iz dojke i/ili iz regionalnih limfnih čvorova, koje još nisu stvorile vidljive udaljene metastaze. Temelji se na kemoterapiji sa ili bez ciljane biološke terapije, na endokrinoj terapiji, ponekad u kombinaciji sa zračenjem, obično nakon kirurškog zahvata. Cilj je smanjiti stopu povratka bolesti i produžiti život bolesnika

Iatrogenic Spinal Cord Injury Resulting From Cervical Spine Surgery.

STUDY DESIGN: Retrospective cohort study of prospectively collected data. OBJECTIVE: To examine the incidence of iatrogenic spinal cord injury following elective cervical spine surgery. METHODS: A retrospective multicenter case series study involving 21 high-volume surgical centers from the AOSpine North America Clinical Research Network was conducted. Medical records for 17 625 patients who received cervical spine surgery (levels from C2 to C7) between January 1, 2005, and December 31, 2011, were reviewed to identify occurrence of iatrogenic spinal cord injury. RESULTS: In total, 3 cases of iatrogenic spinal cord injury following cervical spine surgery were identified. Institutional incidence rates ranged from 0.0% to 0.24%. Of the 3 patients with quadriplegia, one underwent anterior-only surgery with 2-level cervical corpectomy, one underwent anterior surgery with corpectomy in addition to posterior surgery, and one underwent posterior decompression and fusion surgery alone. One patient had complete neurologic recovery, one partially recovered, and one did not recover motor function. CONCLUSION: Iatrogenic spinal cord injury following cervical spine surgery is a rare and devastating adverse event. No standard protocol exists that can guarantee prevention of this complication, and there is a lack of consensus regarding evaluation and treatment when it does occur. Emergent imaging with magnetic resonance imaging or computed tomography myelography to evaluate for compressive etiology or malpositioned instrumentation and avoidance of hypotension should be performed in cases of intraoperative and postoperative spinal cord injury

20-Hydroxycholecalciferol, Product of Vitamin D3 Hydroxylation by P450scc, Decreases NF-κB Activity by Increasing IκBα Levels in Human Keratinocytes

The side chain of vitamin D3 is hydroxylated in a sequential manner by cytochrome P450scc (CYP11A1) to form 20-hydroxycholecalciferol, which can induce growth arrest and differentiation of both primary and immortalized epidermal keratinocytes. Since nuclear factor-κB (NF-κB) plays a pivotal role in the regulation of cell proliferation, differentiation and apoptosis, we examined the capability of 20-hydroxycholecalciferol to modulate the activity of NF-κB, using 1,25-dihydroxycholecalciferol (calcitriol) as a positive control. 20-hydroxycholecalciferol inhibits the activation of NFκB DNA binding activity as well as NF-κB-driven reporter gene activity in keratinocytes. Also, 20-hydroxycholecalciferol induced significant increases in the mRNA and protein levels of the NF-κB inhibitor protein, IκBα, in a time dependent manner, while no changes in total NF-κB-p65 mRNA or protein levels were observed. Another measure of NF-κB activity, p65 translocation from the cytoplasm into the nucleus was also inhibited in extracts of 20-hydroxycholecalciferol treated keratinocytes. Increased IκBα was concomitantly observed in cytosolic extracts of 20-hydroxycholecalciferol treated keratinocytes, as determined by immunoblotting and immunofluorescent staining. In keratinocytes lacking vitamin D receptor (VDR), 20-hydroxycholecalciferol did not affect IκBα mRNA levels, indicating that it requires VDR for its action on NF-κB activity. Comparison of the effects of calcitrol, hormonally active form of vitamin D3, with 20-hydrocholecalciferol show that both agents have a similar potency in inhibiting NF-κB. Since NF-κB is a major transcription factor for the induction of inflammatory mediators, our findings indicate that 20-hydroxycholecalciferol may be an effective therapeutic agent for inflammatory and hyperproliferative skin diseases