Interleukin 17 (IL-17) has a key role in inflammatory responses. Increased serum concentrations of IL-17 have been reported in patients with different types of cancer. Some studies suggest antitumor ...activity of IL-17 while others speak in favor of its association with poorer prognosis. The lack of data on IL-17 behavior
hinders the efforts to clarify the exact role of IL-17 in breast cancer patients and precludes the usage of IL-17 as potential therapeutic target.
The study included 118 patients with early invasive breast cancer. The serum concentration of IL-17A was measured before surgery and during adjuvant treatment and compared with healthy controls. The correlation of serum IL-17A concentration and different clinical and pathological parameters, including IL-17A expression in the corresponding tumor tissue samples, was analyzed.
Significantly higher serum concentrations of IL-17A were found in women with early breast cancer before surgery, but also during adjuvant treatment in comparison to healthy controls. No significant correlation to tumor tissue IL-17A expression was observed. There was a significant postoperative decrease of serum IL-17A concentrations even in patients with relatively lower preoperative values. A significant negative correlation was found between serum IL-17A concentrations and the tumor estrogen receptor expression.
The results suggest that the immune response in early breast cancer is mediated by IL-17A, particularly in triple-negative breast cancer. IL-17A-mediated inflammatory response subsides postoperatively, but IL-17A concentrations remain elevated compared to the values in healthy controls, even after the removal of the tumor.
Correlations between development of hand-foot syndrome (HFS) and efficacy in patients receiving capecitabine (CAP)-containing therapy are reported in the literature. We explored the relationship ...between HFS and efficacy in patients receiving CAP plus bevacizumab (BEV) in the TURANDOT randomised phase III trial.
Patients with HER2-negative locally recurrent/metastatic breast cancer (LR/mBC) who had received no prior chemotherapy for LR/mBC were randomised to BEV plus paclitaxel or BEV-CAP until disease progression or unacceptable toxicity. This analysis included patients randomised to BEV-CAP who received ⩾1 CAP dose. Potential associations between HFS and both overall survival (OS; primary end point) and progression-free survival (PFS; secondary end point) were explored using Cox proportional hazards analyses with HFS as a time-dependent covariate (to avoid overestimating the effect of HFS on efficacy). Landmark analyses were also performed.
Among 277 patients treated with BEV-CAP, 154 (56%) developed HFS. In multivariate analyses, risk of progression or death was reduced by 44% after the occurrence of HFS; risk of death was reduced by 56%. The magnitude of effect on OS increased with increasing HFS grade. In patients developing HFS within the first 3 months, median PFS from the 3-month landmark was 10.0 months vs 6.2 months in patients without HFS. Two-year OS rates were 63% and 44%, respectively.
This exploratory analysis indicates that HFS occurrence is a strong predictor of prolonged PFS and OS in patients receiving BEV-CAP for LR/mBC. Early appearance of HFS may help motivate patients to continue therapy.
Unexpected differences in Ki-67 values among HER2 & ER/PgR defined subgroups were found. This study aims to detect possible subdivisions beyond the conventional breast cancer types.
One thousand one ...hundred eighty consecutive patients with invasive ductal breast carcinoma were included and distributed in 16 subgroups (four HER2 phenotypes (0+, 1+, 2+ and 3+) times four ER/PgR phenotypes). Complex distributions of Ki-67 values were tested by expectation maximization (EM) clustering.
Pooled Ki67 values of all patients showed the presence of three EM clusters (defined as LMA-low mitotic activity, IMA-intermediate mitotic activity and HMA-high mitotic activity) with expected mean Ki-67 values of 1.17%, 40.45% and 77.79%, respectively. Only ER-PgR- tumors significantly dispersed in three clusters (29.75% tumors in LMA, 46.95% in IMA and 23.30% in the HMA cluster), while almost no detected HMA tumors were of ER + PgR+ or ER + PgR- phenotypes. Among 799 ER + PgR+ patients distribution in clusters was HER2 dependent (p = 0.000243), due to increased number of IMA HER2 3+ tumors on the expense of LMA HER2 3+ tumors (52 IMA out of 162 HER2 3+ patients versus113 IMA out of 637 HER2 < 3+ patients). This was not found among ER + PgR- patients (p = 0.186968). Among ER-PgR- patients, HER2 overexpression also increased number of IMA tumor, but by reducing the number of HMA tumors (p < 0.000001). Here, difference between HER2 absent (0+) and HER2 3+ patients was evident (10 HMA out of 125 HER2 3+ patients versus 42 HMA out of 103 HER2 0+ patients).
Results suggest that distributions of breast cancers in three clusters of mitotic activity depend on different mechanisms for ER + PgR+ and ER negative tumors. Although HER2 overexpression increases number of IMA tumors in both settings, in the former it is done by reducing number of LMA tumors, while in the latter it reduces the number of HMA tumors. Mitotic activity of ER + PgR- tumors seems unrelated to the HER2 status, possibly as an indicator that ER dysfunctionality in cancers that lack PgR expression. Among ER negative tumors, the absence of HER2 (0+) might be as important as the HER2 overexpression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To investigate efficacy and safety of cetuximab combined with two chemotherapy regimens in patients with unresectable metastatic colorectal cancer (mCRC).
Randomized patients received cetuximab with ...5-fluorouracil (5-FU), folinic acid (FA) and oxaliplatin (FOLFOX) 6 (arm A, n = 74) or 5-FU, FA and irinotecan (FOLFIRI) (arm B, n = 77). KRAS mutation status was determined retrospectively in a subset of tumors (n = 117).
No significant difference was found between treatment arms A and B in the progression-free survival (PFS) rate at 9 mo, 45% vs 34%; median PFS, 8.6 mo vs 8.3 mo hazard ratio (HR) = 1.06; overall response rate (ORR) 43% vs 45% odds ratio (OR) = 0.93 and median overall survival (OS), 17.4 mo vs 18.9 mo (HR = 0.98). Patients with KRAS wild-type tumors demonstrated improved PFS (HR = 0.55, P = 0.0051), OS, (HR = 0.62, P = 0.0296) and ORR (53% vs 36%) and in arm A, improved PFS (HR = 0.49, P = 0.0196), OS (HR = 0.48, P = 0.0201) and ORR (56% vs 30%), compared with patients with KRAS mutated tumors. In arm B no significant differences were found in efficacy by KRAS mutation status. Treatment in arms A and B was generally well tolerated.
This study confirms that combinations of cetuximab with FOLFOX6 or FOLFIRI are effective and significantly improve clinical outcome in KRAS wild-type compared with KRAS mutated mCRC.
Triple-negative breast cancer (TNBC) occurs in around one-sixth of all breast cancer (BC) patients, with the most aggressive behavior and worst prognosis of all BC subtypes. It is a heterogeneous ...disease, with specific molecular characteristics and natural dynamics of early recurrence and fast progression. Due to the lack of biomarkers or any valid treatment targets, it can only be treated with classic cytotoxic chemotherapy. We analyzed a cohort of 152 patients, median age 58 years, diagnosed with and treated for early stage TNBC at the university Hospital for Tumors, Sestre milosrdnice university Hospital Centre, Zagreb, Croatia, during the 2009-2012 period. Patients were treated with primary surgical approach, adjuvant chemotherapy and adjuvant irradiation. We observed a relatively large proportion of locally advanced TNBC at diagnosis, with large tumor size and nodal involvement, with high grade and high proliferation index Ki67. Patient age, tumor size and lymph node involvement, as expected, were significant and clinically most important prognostic factors for 5-year disease-free survival (67%; 95% CI 60%-75%) and overall absolute survival rate (74%; 95% CI 66%-81%). Key words: Triple negative breast cancer; Early disease; Adjuvant treatment; Tumor size; Lymph node; Disease free survival; Overall survival; Prognostic factor
Tumor stimulates specific innate and acquired immune mechanisms. Main carriers of body’s immune response to tumor are T lymphocytes and main mechanism is killing of tumor cells by cytotoxic T ...lymphocytes CD8 +. In some cases, immune system can also have a protumor role, which is a paradox, given that it is known that the inflammatory state promotes tumor growth. One of the major characteristics of tumors is the evading of immune response, in particular by mechanisms of inhibition of active antitumor immune response via two major physiological inhibitory signals, CTLA-4 and PD1 / PDL1. Blockade of these checkpoints, that are T cell inhibitory mechanisms, has recently yielded best results in an immunotherapy approach to cancer treatment. Immune infiltrate in the tumor, as evidence of existence of an active intrinsic response of the organism, is heterogeneous, and composition often differs between different tumors and tumor cells, and mainly divides into two main cell lines: lymphoid and myeloid. On type of cell lines in the immune infiltrate and their activation and orientation depends the clinical response in different tumors. It is well known that immune infiltrate, especially tumorinfiltrating lymphocytes (TILs), can be predictive of response to therapy and have a prognostic role. In some solid tumors they are a good sign, while in some they signal worse prognosis. Numerous studies have evaluated role of lymphocytic infiltrate in breast cancer (BC) and, based on this knowledge, first consensus on standardization of TILs evaluation in solid tumors has been established on the BC model. Prognostic role of TILs in triple-negative breast cancer has received the most attention.
Breast cancer is the most common malignancy in females. Despite its well-established prognostic factors, our prognostic ability at an individual patient level remains limited. In this study, the ...immunohistochemical expression of B-Myb and DNA topoisomerase 2-alpha (Topo2a) was analyzed in primary tumors to identify patients with a higher risk of disease recurrence after adjuvant chemotherapy for early invasive breast cancer. We analyzed a cohort of 215 early invasive breast cancer patients having undergone surgery from 2002 to 2003 at the Zagreb University Hospital Centre, including 153 patients treated with adjuvant chemotherapy. All of them were followed-up prospectively for at least ten years according to routine institutional practice. Statistically significant correlations were found between B-Myb and Topo2a expression levels and particular well-established prognostic factors. B-Myb expression was lower in estrogen receptor (ER)-positive tumors (p=0.0773), whereas larger tumors and those with positive lymphovascular invasion displayed a statistically significantly higher B-Myb expression (p=0.0409 and p=0.0196). Higher tumor grade indicated higher Topo2a values (p=0.0102 and p=0.0069). The subgroup with the expression of both proteins above the median value had an almost statistically significantly (p=0.0613) inferior prognosis compared to the rest of the cohort. Study results showed the B-Myb and Topo2a expression to have a prognostic value in breast cancer patients after adjuvant chemotherapy, which should be additionally explored in future studies in a larger patient cohort.
Androgen receptors (AR) are ligand-dependent nuclear transcription factors. These are steroid receptors, similar to estrogen receptors (ER). They are expressed in numerous cells in the body, with ...different constructive roles. AR signalling can be involved in the development of a variety of human malignant tumors, such as prostate cancer, bladder, liver, salivary glands, kidney, lung, melanoma, sarcoma, breast cancer, and many others. The role of AR is most clear and today best explained in prostate cancer. The mechanism of AR signalling in other human epithelial tumors is still quite unclear and the effects are different to entirely opposite in different tumors. In breast cancer, AR are the most commonly expressed receptors, but still with an incompletely clear role, prognostic and predictive significance. The expression of AR in triple-negative breast cancer (TNBC) is highly variable. Despite the marked differences in the results of the various analyzes, they appear to have a beneficial effect on the prognosis and are potentially the target of antihormone therapy for treatment of TNBC in the future.
Prolonged or repeated stimulation of Toll-like receptor (TLR) 4 leads to hyporesponsiveness of monocyte-derived macrophages, which seems to be a hallmark of immunosuppression related to sepsis and ...cancer. Two negative regulators of TLR-4 signaling are IL-1 receptor-associated kinase M and B-cell leukemia 3. Here, we demonstrate that the expression of both proteins is inhibited when the TLR-7/TLR-8 agonist CL097 is added to monocyte cultures despite costimulation with the TLR-4 agonist LPS or hyaluronic acid. Reduction of IL-1 receptor-associated kinase M and B-cell leukemia 3 was paralleled by a significant increased cytokine induction of TNF-alpha, IL-10, and IL-12 observed after intracellular and extracellular TLR stimulation. In ex vivo stimulated whole blood of patients who have prolonged sepsis or metastatic cancer, TLR-7/TLR-8 agonists retained their ability of increased stimulation of TNF-alpha. These data might add to the understanding of sepsis and cancer-associated immune suppression in men.
Abstract only
e16507
Background: The aim was to define IHC changes between the two subsequent urinary bladder cancers (UBC). Methods: IHC data on EGFR, HER2, HER3, Ki-67, MLH1, MSH2, MSH6 and PMS2 in ...113 UHC from 24 male and 9 female patients (1 to six recurrences) were used. Except for the Ki-67 value, other markers were stratified: “0” for no positive cells; “1” < = 10% positive cells; “2” 1%-30% positive cells; and “3” 31%-100% positive cells. Data of consecutive tumors were paired in 80 processes of recurrence (PoR). Changes between the latter and the former tumor were calculated: in +/- % for Ki-67 values, and as integer sums of absolute changes in expression for HER markers and for Lynch markers. EM clustering was applied for recognition of relevant IHC changes. Results: Three aspects were tested: the speed of recurrence, was it the first, or later recurrence and whether PoRs depended on the total number of tumors in that patient. Early and late PoRs clustered along the Lynch score, while the intermediate clustered along the delta Ki-67 value. The first PoRs clustered along the HER score and all subsequent PoRs depended on the Lynch score. Conclusions: Even in this limited group of patients Lynch and HER markers showed complex differences between early and late recurrent tumors. The speed of the recurrence and changes of IHC features depended mainly on the rate of change in Lynch markers, suggesting that they should be tested as predictors of UBC recurrence.Table: see text
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