Health-related quality of life anticipated with different management strategies for febrile neutropenia in adult cancer patients

PURPOSE: To describe anticipated health-related quality of life (HRQL) for different hypothetical strategies of febrile neutropenia (FN) management in adult cancer patients. METHODS: Seventy-eight adult cancer patients were enrolled. Our study considered four different hypothetical treatment strategies for FN: (1) entire inpatient management with intravenous (IV) antibiotics; (2) oral treatment at home after an initial observation in hospital with IV antibiotics; (3) entire outpatient management with IV antibiotics; and (4) entire outpatient management with oral antibiotics. Initially, patients were asked to rank the different treatment strategies for FN based on their personal preference. Subsequently, HRQL was rated using visual analog scale (VAS), time trade-off (TTO), and willingness-to-pay (WTP). RESULTS: Seventy-five percent of all respondents preferred an outpatient strategy for FN (36% oral, 21% intravenous, 18% early discharge). Further, outpatient strategies were associated with higher mean VAS scores (possible range 0-10) (oral: 6.1 (standard deviation (SD) 3.1); intravenous: 6.2 (SD 2.2); early discharge: 5.7 (SD 2.1)) as compared to inpatient care (5.3 (SD 2.9)). On the aggregate level, patients were willing to give up between 9 and 10 weeks of their life (TTO; corresponding to <1% of remaining life expectancy) and to pay between $255 and $327 Canadian dollars (WTP) to avoid treatment in hospital. CONCLUSIONS: Our study indicates that the majority of adult cancer patients would prefer an outpatient strategy for FN. However, patients' preferences vary substantially at the individual level. Implementation of outpatient strategies into routine clinical practice should consider this variability.

Suicide in breast cancer patients: an individual-centered approach provides insight beyond epidemiology

Epidemiologic studies have identified increased suicide rates among breast cancer (BC) patients. The population-based approach, however, has considerable methodic shortcomings. None of the studies have been carried out in a prospective manner and none reported suicide rates from a country in which physician-assisted suicide (PAS) is legal.

Tumor architecture exerts no bias on nuclear grading in breast cancer diagnosis

We recently reported that nuclear grading in prostate cancer is subject to a strong confirmation bias induced by the tumor architecture. We now wondered whether a similar bias governs nuclear grading in breast carcinoma. An unannounced test was performed at a pathology conference. Pathologists were asked to grade nuclei in a PowerPoint presentation. Circular high power fields of 27 invasive ductal carcinomas were shown, superimposed over low power background images of either tubule-rich or tubule-poor carcinomas. We found (a) that diagnostic reproducibility of nuclear grades was poor to moderate (weighed kappa values between 0.07 and 0.54, 27 cases, 44 graders), but (b) that nuclear grades were not affected by the tumor architecture. We speculate that the categorized grading in breast cancer, separating tubule formation, nuclear pleomorphism, and mitotic figure counts in a combined three tier score, prevents the bias that architecture exerts on nuclear grades in less well-controlled situations.

What was I thinking? Eye-tracking experiments underscore the bias that architecture exerts on nuclear grading in prostate cancer

We previously reported that nuclear grade assignment of prostate carcinomas is subject to a cognitive bias induced by the tumor architecture. Here, we asked whether this bias is mediated by the non-conscious selection of nuclei that "match the expectation" induced by the inadvertent glance at the tumor architecture. 20 pathologists were asked to grade nuclei in high power fields of 20 prostate carcinomas displayed on a computer screen. Unknown to the pathologists, each carcinoma was shown twice, once before a background of a low grade, tubule-rich carcinoma and once before the background of a high grade, solid carcinoma. Eye tracking allowed to identify which nuclei the pathologists fixated during the 8 second projection period. For all 20 pathologists, nuclear grade assignment was significantly biased by tumor architecture. Pathologists tended to fixate on bigger, darker, and more irregular nuclei when those were projected before kigh grade, solid carcinomas than before low grade, tubule-rich carcinomas (and vice versa). However, the morphometric differences of the selected nuclei accounted for only 11% of the architecture-induced bias, suggesting that it can only to a small part be explained by the unconscious fixation on nuclei that "match the expectation". In conclusion, selection of « matching nuclei » represents an unconscious effort to vindicate the gravitation of nuclear grades towards the tumor architecture.

Negative regulation of NF-κB by the ING4 tumor suppressor in breast cancer

Nuclear Factor kappa B (NF-κB) is a key mediator of normal immune response but contributes to aggressive cancer cell phenotypes when aberrantly activated. Here we present evidence that the Inhibitor of Growth 4 (ING4) tumor suppressor negatively regulates NF-κB in breast cancer. We surveyed primary breast tumor samples for ING4 protein expression using tissue microarrays and a newly generated antibody. We found that 34% of tumors expressed undetectable to low levels of the ING4 protein (n = 227). Tumors with low ING4 expression were frequently large in size, high grade, and lymph node positive, suggesting that down-regulation of ING4 may contribute to breast cancer progression. In the same tumor set, we found that low ING4 expression correlated with high levels of nuclear phosphorylated p65/RelA (p-p65), an activated form of NF-κB (p = 0.018). Fifty seven percent of ING4-low/p-p65-high tumors were lymph node-positive, indicating a high metastatic tendency of these tumors. Conversely, ectopic expression of ING4 inhibited p65/RelA phosphorylation in T47D and MCF7 breast cancer cells. In addition, ING4 suppressed PMA-induced cell invasion and NF-κB-target gene expression in T47D cells, indicating that ING4 inhibited NF-κB activity in breast cancer cells. Supportive of the ING4 function in the regulation of NF-κB-target gene expression, we found that ING4 expression levels inversely correlated with the expression of NF-κB-target genes in primary breast tumors by analyzing public gene expression datasets. Moreover, low ING4 expression or high expression of the gene signature composed of a subset of ING4-repressed NF-κB-target genes was associated with reduced disease-free survival in breast cancer patients. Taken together, we conclude that ING4 negatively regulates NF-κB in breast cancer. Consequently, down-regulation of ING4 leads to activation of NF-κB, contributing to tumor progression and reduced disease-free patient survival in breast cancer.

[Assessment of proliferation: core biopsy or resection specimen? Discrepancies in breast cancer with low and high proliferation]

The assessment of the proliferation fraction is becoming more and more important; however, there is no consensus concerning optimal validation. Depending on the institute the proliferation fraction is determined either from a core biopsy (SB) or resection specimen (OP).

Human epidermal growth factor receptor-2 gene amplification in gastric cancer using tissue microarray technology

To assess human epidermal growth factor receptor-2 (HER2)-status in gastric cancer and matched lymph node metastases by immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH).

Role of KCNMA1 in breast cancer

KCNMA1 encodes the α-subunit of the large conductance, voltage and Ca(2+)-activated (BK) potassium channel and has been reported as a target gene of genomic amplification at 10q22 in prostate cancer. To investigate the prevalence of the amplification in other human cancers, the copy number of KCNMA1 was analyzed by fluorescence-in-situ-hybridization (FISH) in 2,445 tumors across 118 different tumor types. Amplification of KCNMA1 was restricted to a small but distinct fraction of breast, ovarian and endometrial cancer with the highest prevalence in invasive ductal breast cancers and serous carcinoma of ovary and endometrium (3-7%). We performed an extensive analysis on breast cancer tissue microarrays (TMA) of 1,200 tumors linked to prognosis. KCNMA1 amplification was significantly associated with high tumor stage, high grade, high tumor cell proliferation, and poor prognosis. Immunofluorescence revealed moderate or strong KCNMA1 protein expression in 8 out of 9 human breast cancers and in the breast cancer cell line MFM223. KCNMA1-function in breast cancer cell lines was confirmed by whole-cell patch clamp recordings and proliferation assays, using siRNA-knockdown, BK channel activators such as 17ß-estradiol and the BK-channel blocker paxilline. Our findings revealed that enhanced expression of KCNMA1 correlates with and contributes to high proliferation rate and malignancy of breast cancer.

Prognostic impact of β-2-microglobulin expression in colorectal cancers stratified by mismatch repair status

β-2-microglobulin (B2M) is essential for antigen presentation, yet may also possess proto-oncogenic properties.

Effect of EpCAM, CD44, CD133 and CD166 expression on patient survival in tumours of the ampulla of Vater

Carcinomas of the Vaterian system are rare and presumably arise from pre-existing adenomas. According to the cancer stem cell (CSC) hypothesis, only a small subset of tumor cells has the ability to initiate and develop tumor growth. In colorectal cancer, CD44, CD133, CD166 and EpCAM have been proposed to represent CSC marker proteins and their expression has been shown to correlate with patient survival.

Tissue-based proteomics reveals FXYD3, S100A11 and GSTM3 as novel markers for regional lymph node metastasis in colon cancer

Regional lymph node metastasis negatively affects prognosis in colon cancer patients. The molecular processes leading to regional lymph node metastasis are only partially understood and proteomic markers for metastasis are still scarce. Therefore, a tissue-based proteomic approach was undertaken for identifying proteins associated with regional lymph node metastasis. Two complementary tissue-based proteomic methods have been employed. MALDI imaging was used for identifying small proteins (≤25 kDa) in situ and label-free quantitative proteomics was used for identifying larger proteins. A tissue cohort comprising primary colon tumours without metastasis (UICC II, pN0, n = 21) and with lymph node metastasis (UICC III, pN2, n = 33) was analysed. Subsequent validation of identified proteins was done by immunohistochemical staining on an independent tissue cohort consisting of primary colon tumour specimens (n = 168). MALDI imaging yielded ten discriminating m/z species, and label-free quantitative proteomics 28 proteins. Two MALDI imaging-derived candidate proteins (FXYD3 and S100A11) and one from the label-free quantitative proteomics (GSTM3) were validated on the independent tissue cohort. All three markers correlated significantly with regional lymph node metastasis: FXYD3 (p = 0.0110), S100A11 (p = 0.0071), and GSTM3 (p = 0.0173). FXYD3 and S100A11 were more highly expressed in UICC II patient tumour tissues. GSTM3 was more highly expressed in UICC III patient tumour tissues. By our tissue-based proteomic approach, we could identify a large panel of proteins which are associated with regional lymph node metastasis and which have not been described so far. Here we show that novel markers for regional lymph metastasis can be identified by MALDI imaging or label-free quantitative proteomics and subsequently validated on an independent tissue cohort. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Clinically significant bleeding in incurable cancer patients: effectiveness of hemostatic radiotherapy

Background This study was performed to evaluate the outcome after hemostatic radiotherapy (RT) of significant bleeding in incurable cancer patients. Methods Patients treated by hemostatic RT between November 2006 and February 2010 were retrospectively analyzed. Bleeding was assessed according to the World Health Organization (WHO) scale (grade 0 = no bleeding, 1 = petechial bleeding, 2 = clinically significant bleeding, 3 = bleeding requiring transfusion, 4 = bleeding associated with fatality). The primary endpoint was bleeding at the end of RT. Key secondary endpoints included overall survival (OS) and acute toxicity. The bleeding score before and after RT were compared using the Wilcoxon signed rank test. Time to event endpoints were estimated using the Kaplan Meier method. Results Overall 62 patients were analyzed including 1 patient whose benign cause of bleeding was pseudomyxoma peritonei. Median age was 66 (range, 37–93) years. Before RT, bleeding was graded as 2 and 3 in 24 (39%) and 38 (61%) patients, respectively. A median dose of 20 (range, 5–45) Gy of hemostatic RT was applied to the bleeding site. At the end of RT, there was a statistically significant difference in bleeding (p < 0.001); it was graded as 0 (n = 39), 1 (n = 12), 2 (n = 6), 3 (n = 4) and 4 (n = 1). With a median follow-up of 19.3 (range, 0.3-19.3) months, the 6-month OS rate was 43%. Forty patients died (65%); 5 due to bleeding. No grade 3 or above acute toxicity was observed. Conclusions Hemostatic RT seems to be a safe and effective treatment for clinically and statistically significantly reducing bleeding in incurable cancer patients.

Primary prophylactic colony-stimulating factors for the prevention of chemotherapy-induced febrile neutropenia in breast cancer patients

High-dose or dose-intensive cytotoxic chemotherapy often causes myelosuppression and severe neutropenia among cancer patients. Severe neutropenia accompanied by fever, named febrile neutropenia (FN), is the most serious manifestation of neutropenia usually requiring hospitalization and intravenous antibiotics. FN and neutropenia can lead to chemotherapy treatment delays or dose reductions, which potentially compromises the effectiveness of cancer treatment and prospects for a cure. Granulocyte-macrophage (GM) and granulocyte colony-stimulating factors (G-CSFs) are administered during chemotherapy in order to prevent or reduce the incidence or the duration of FN and neutropenia.