Background No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. Methods In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. Results At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. Conclusions In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.

/pdf/sorafenib-in-advanced-hepatocellular-carcinoma-3xdq9sbovw.pdf

Sorafenib in Advanced Hepatocellular Carcinoma

Background
Decision aids are intended to help people participate in decisions that involve weighing the benefits and harms of treatment options often with scientific uncertainty.

Objectives
To assess the effects of decision aids for people facing treatment or screening decisions.

Search methods
For this update, we searched from 2009 to June 2012 in MEDLINE; CENTRAL; EMBASE; PsycINFO; and grey literature. Cumulatively, we have searched each database since its start date including CINAHL (to September 2008).

Selection criteria
We included published randomized controlled trials of decision aids, which are interventions designed to support patients' decision making by making explicit the decision, providing information about treatment or screening options and their associated outcomes, compared to usual care and/or alternative interventions. We excluded studies of participants making hypothetical decisions.

Data collection and analysis
Two review authors independently screened citations for inclusion, extracted data, and assessed risk of bias. The primary outcomes, based on the International Patient Decision Aid Standards (IPDAS), were:

A) 'choice made' attributes;

B) 'decision-making process' attributes.

Secondary outcomes were behavioral, health, and health-system effects. We pooled results using mean differences (MD) and relative risks (RR), applying a random-effects model.

Main results
This update includes 33 new studies for a total of 115 studies involving 34,444 participants. For risk of bias, selective outcome reporting and blinding of participants and personnel were mostly rated as unclear due to inadequate reporting. Based on 7 items, 8 of 115 studies had high risk of bias for 1 or 2 items each.

Of 115 included studies, 88 (76.5%) used at least one of the IPDAS effectiveness criteria: A) 'choice made' attributes criteria: knowledge scores (76 studies); accurate risk perceptions (25 studies); and informed value-based choice (20 studies); and B) 'decision-making process' attributes criteria: feeling informed (34 studies) and feeling clear about values (29 studies).

A) Criteria involving 'choice made' attributes:

Compared to usual care, decision aids increased knowledge (MD 13.34 out of 100; 95% confidence interval (CI) 11.17 to 15.51; n = 42). When more detailed decision aids were compared to simple decision aids, the relative improvement in knowledge was significant (MD 5.52 out of 100; 95% CI 3.90 to 7.15; n = 19). Exposure to a decision aid with expressed probabilities resulted in a higher proportion of people with accurate risk perceptions (RR 1.82; 95% CI 1.52 to 2.16; n = 19). Exposure to a decision aid with explicit values clarification resulted in a higher proportion of patients choosing an option congruent with their values (RR 1.51; 95% CI 1.17 to 1.96; n = 13).

B) Criteria involving 'decision-making process' attributes:

Decision aids compared to usual care interventions resulted in:

a) lower decisional conflict related to feeling uninformed (MD -7.26 of 100; 95% CI -9.73 to -4.78; n = 22) and feeling unclear about personal values (MD -6.09; 95% CI -8.50 to -3.67; n = 18);

b) reduced proportions of people who were passive in decision making (RR 0.66; 95% CI 0.53 to 0.81; n = 14); and

c) reduced proportions of people who remained undecided post-intervention (RR 0.59; 95% CI 0.47 to 0.72; n = 18).

Decision aids appeared to have a positive effect on patient-practitioner communication in all nine studies that measured this outcome. For satisfaction with the decision (n = 20), decision-making process (n = 17), and/or preparation for decision making (n = 3), those exposed to a decision aid were either more satisfied, or there was no difference between the decision aid versus comparison interventions. No studies evaluated decision-making process attributes for helping patients to recognize that a decision needs to be made, or understanding that values affect the choice.

C) Secondary outcomes

Exposure to decision aids compared to usual care reduced the number of people of choosing major elective invasive surgery in favour of more conservative options (RR 0.79; 95% CI 0.68 to 0.93; n = 15). Exposure to decision aids compared to usual care reduced the number of people choosing to have prostate-specific antigen screening (RR 0.87; 95% CI 0.77 to 0.98; n = 9). When detailed compared to simple decision aids were used, fewer people chose menopausal hormone therapy (RR 0.73; 95% CI 0.55 to 0.98; n = 3). For other decisions, the effect on choices was variable.

The effect of decision aids on length of consultation varied from 8 minutes shorter to 23 minutes longer (median 2.55 minutes longer) with 2 studies indicating statistically-significantly longer, 1 study shorter, and 6 studies reporting no difference in consultation length. Groups of patients receiving decision aids do not appear to differ from comparison groups in terms of anxiety (n = 30), general health outcomes (n = 11), and condition-specific health outcomes (n = 11). The effects of decision aids on other outcomes (adherence to the decision, costs/resource use) were inconclusive.

Authors' conclusions
There is high-quality evidence that decision aids compared to usual care improve people's knowledge regarding options, and reduce their decisional conflict related to feeling uninformed and unclear about their personal values. There is moderate-quality evidence that decision aids compared to usual care stimulate people to take a more active role in decision making, and improve accurate risk perceptions when probabilities are included in decision aids, compared to not being included. There is low-quality evidence that decision aids improve congruence between the chosen option and the patient's values.

New for this updated review is further evidence indicating more informed, values-based choices, and improved patient-practitioner communication. There is a variable effect of decision aids on length of consultation. Consistent with findings from the previous review, decision aids have a variable effect on choices. They reduce the number of people choosing discretionary surgery and have no apparent adverse effects on health outcomes or satisfaction. The effects on adherence with the chosen option, cost-effectiveness, use with lower literacy populations, and level of detail needed in decision aids need further evaluation. Little is known about the degree of detail that decision aids need in order to have a positive effect on attributes of the choice made, or the decision-making process.

/pdf/decision-aids-for-people-facing-health-treatment-or-1j1706q17l.pdf

Decision aids for people facing health treatment or screening decisions

CA : A Cancer Journal for Clinicians

Background Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease. Methods In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group. Results Patients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patie...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa066838

Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.

https://rihuc.huc.min-saude.pt/bitstream/10400.4/1818/1/renal%20cell%20carcinoma.pdf

EAU Guidelines on Renal Cell Carcinoma: 2014 Update

We are reporting a case of a 55-year-old woman who was diagnosed as having a non-functioning pancreatic neuroendocrine neoplasm (NF-PNEN), the World Health Organization (WHO) low grade (G1) with liver metastases. In the staging process the positron emission tomography - computed tomography with Fluorine-18-Fluorodeoxyglucose (F-FDG PET-CT) and spiral CT then the gallium-DOTA-octreotate positron emission tomography - computer tomography (⁶⁸Ga-DOTATATE PET-CT) shown difference in burden of disease. In first line therapy, everolimus (Afinitor®, Novartis Pharma GmbH, Germany) at the oral dose of 10 mg once daily and octreotide long-acting release (Sandostatin LAR®) 30 mg i.m. every 4 weeks were administered. Then, due to disease progression - radioisotope therapy with b-emitter Yttrium-90 (⁹⁰Y). Based on this experience and on the review of the literature, we recommend that the discrepancy between the imaging studies could be due to heterogeneity of proliferation rate and somatostatin receptors (SSTR) expression within a primary PNEN and metastases. Therefore in such cases of advanced PNEN WHO G1 in the lack of response to everolimus and octreotide LAR administration isotope therapy without a prior chemotherapy should be considered as a palliative treatment according to ESMO Clinical Practice Guidelines and Polish Network of Neuroendocrine Tumors.

/pdf/problems-of-diagnostic-assessment-in-advanced-pancreatic-vvplw3pp8y.pdf

Problems of diagnostic assessment in advanced pancreatic neuroendocrine neoplasm and treatment implications: a case report and literature review.

Natural compounds, such as resveratrol (Res), are currently used as adjuvants for anticancer therapies. To evaluate the effectiveness of Res for the treatment of ovarian cancer (OC), we screened the response of various OC cell lines to the combined treatment with cisplatin (CisPt) and Res. We identified A2780 cells as the most synergistically responding, thus optimal for further analysis. Because hypoxia is the hallmark of the solid tumor microenvironment, we compared the effects of Res alone and in combination with CisPt in hypoxia (pO2 = 1%) vs. normoxia (pO2 = 19%). Hypoxia caused an increase (43.2 vs. 5.0%) in apoptosis and necrosis (14.2 vs. 2.5%), reactive oxygen species production, pro-angiogenic HIF-1α (hypoxia-inducible factor-1α) and VEGF (vascular endothelial growth factor), cell migration, and downregulated the expression of ZO1 (zonula occludens-1) protein in comparison to normoxia. Res was not cytotoxic under hypoxia in contrast to normoxia. In normoxia, Res alone or CisPt+Res caused apoptosis via caspase-3 cleavage and BAX, while in hypoxia, it reduced the accumulation of A2780 cells in the G2/M phase. CisPt+Res increased levels of vimentin under normoxia and upregulated SNAI1 expression under hypoxia. Thus, various effects of Res or CisPt+Res on A2780 cells observed in normoxia are eliminated or diminished in hypoxia. These findings indicate the limitations in using Res as an adjuvant with CisPt therapy in OC.

/pdf/hypoxia-but-not-normoxia-reduces-effects-of-resveratrol-on-2q6gvwei.pdf

Hypoxia, but Not Normoxia, Reduces Effects of Resveratrol on Cisplatin Treatment in A2780 Ovarian Cancer Cells: A Challenge for Resveratrol Use in Anticancer Adjuvant Cisplatin Therapy

kspresja receptora HER2 występuje w 20–30 proc. inwazyjnych raków piersi i w 60 proc. raków śródprzewodowych. U chorych na inwazyjnego raka piersi zaburzenia genu HER2 związane są z bardziej agresywnym przebiegiem choroby, większym prawdopodobieństwem nawrotu i krótszym czasem przeżycia. Trastuzumab (herceptyna) jest przeciwciałem monoklonalnym, skierowanym wybiórczo przeciwko receptorowi błonowemu naskórkowego czynnika wzrostu, HER2. Wprowadzenie tego preparatu do terapii rozsianego raka piersi, wykazującego nadekspresję i/lub amplifikację HER2, pozwoliło zwiększyć udział częściowych i całkowitych remisji nowotworu oraz wydłużyło czas do progresji i czas całkowitego przeżycia. Jedną z częstszych form niepowodzenia leczenia trastuzumabem są pojawiające się w trakcie terapii przerzuty do ośrodkowego układu nerwowego (OUN). Najprawdopodobniej jest to wynikiem nieprzenikania trastuzumabu przez barierę krew-mózg, związane z dużą masą cząsteczkową tej substancji (ok. 145 kDa). Efekt ten może być jednak również spowodowany wydłużeniem czasu przeżycia chorych w wyniku lepszej kontroli innych ognisk choroby nowotworowej, przy równoczesnym rozwoju przerzutów w OUN jako tzw. chronionym obszarze (ang. sanctuary site). Wysuwana jest także hipoteza, że obecność receptora HER2 stanowi czynnik predysponujący do rozwoju przerzutów do OUN. Celem pracy jest omówienie patomechanizmu tego zjawiska oraz jego implikacje kliniczne.

https://www.termedia.pl/Journal/-3/pdf-5776-1?filename=Przerzuty do oorodkowego.pdf

Central nervous system metastases in advanced breast cancer patients treated with trastuzumab

/pdf/cartilage-in-therapy-of-renal-cell-cancer-q4u42kngxj.pdf

Cartilage in therapy of renal cell cancer

Endothelial cells (ECs) select, recognize and stop circulating cells on the vascular endothelium surface which allows homing, making them key players of recruitment selectivity into normal vs pathologic organs. While endothelium organospecificity is the first selectivity level by which ECs interact with extra- and intravasating cells, ECs adapt to environmental signals which strongly influences the surface phenotype of the concerned endothelium. ECs express sets of homing receptors/adhesion molecules, a pattern enabling them to retain or exclude normal or pathologic circulating cells. At EC interactions level, cross-recognitions molecules are endogenous lectins: Selectins, Siglecs, galectins, with their glycosylated ligands. As first interacting partners, they finely tune adhesion by their rapid and dynamic modifications reflecting microenvironment. ECs functions require variability and adaptation to site changes to report the local and temporal biological state. Among modulatory effects which respond to the dynamic reactions needs, post-translational modifications by glycosylation provide the molecular answers orchestrating specific and efficient cell cross-talk. Quantitative and qualitative variations of glycoconjugates composition, in response to microenvironmental pressures is a fast, strongly sensitive means to modulate interactions and molecular reactivity. Mediated by the glycosyltransferases/glycosidases balance, dependent on microenvironmental conditions as tumor hypoxia, glycoconjugate recognitions are responsible for immune cells recruitment in normal conditions with deep consequences in diseases. Deleterious extravasation/intravasation of dysfunctional immune and pathologic cells like metastases, result from similar mechanisms. Consequently, control of glycoconjugates composition, expression and recognitions, open to new therapeutic approaches for the improvement of therapies efficacy. 

Cezary Szczylik

Papers

Problems of diagnostic assessment in advanced pancreatic neuroendocrine neoplasm and treatment implications: a case report and literature review.

Hypoxia, but Not Normoxia, Reduces Effects of Resveratrol on Cisplatin Treatment in A2780 Ovarian Cancer Cells: A Challenge for Resveratrol Use in Anticancer Adjuvant Cisplatin Therapy

Central nervous system metastases in advanced breast cancer patients treated with trastuzumab

Cartilage in therapy of renal cell cancer

Microenvironment-dependent endothelial cells glycosylation influence on angiogenesis and cancer spreading