Mechanisms of tumor necrosis factor-α and interleukin-6 induction during human liver transplantation

In human orthotopic liver transplantation (LTX) intraoperative elevations of TNF-α (> 100 pg/ml) and IL-6 (>800 pg/ml) have been found to correlate with early post-operative rejections and infections respectively. In this study the possible mechanism responsible for the induction of these cytokines has been investigated during liver allografting in 38 recipients. Intraoperative elevations of TNF-α (> 100 pg/ml) were detected in the majority of pre-transplant endotoxin positive recipients (8/12, > 10 endotoxin units/ml), the patients turning endotoxin positive until the end of grafting (3/5), and in a subgroup (6/21 patients), apparently endotoxin negative for the whole operation. Therefore endotoxin (ET) seems to stimulate release of TNF-α in approximately 50% of the patients, whereas sensitized Kupffer graft cells or immediate allograft reactivity of the host are likely to account for the remaining TNF-α positive cases. Elevations of IL-6 > 800 pg/ml) were found in approximately 50% of the TNF-α positive cases, indicating partially independent regulatory pathways for IL-6 induction in the TNF-α negative patients. In agreement with a previous study, 11/13 (85%) of the intraoperative TNF-α positive recipients rejected their grafts within the first 10 days post-operatively. These data demonstrate that ET/infection associated as well as ET independent/reperfusion associated intraoperative TNF-α elevations, promote the initiation of allograft rejection in human liver transplantation. The transient and low endotoxaemia caused by the liver grafting procedure performed without veno-venous bypass seems to be of minor importance in the intraoperative induction of TNF-α

Endocrine therapy and related issues in hormone receptor-positive early breast cancer: a roundtable discussion by the breast cancer therapy expert group (BCTEG)

Purpose: Management of breast cancer is a rapidly evolving field, and, although evidence-based guidelines are available for clinicians to provide direction on critical issues in patient care, clinicians often left to address these issues in the context of community practice situations with their patients. These include the patient’s comorbid conditions, actual versus perceived benefit of treatments, patient’s compliance as well as financial/reimbursement issues, and long-term tolerability of therapy. Methods: A meeting of global oncology experts was convened in January 2017 with the belief that there is a gap in clinical practice guidance on several fundamental issues in breast cancer care, particularly in the community setting, where oncologists may encounter multiple tumor types. The goal was to discuss some of the most important questions in this area and provide some guidance for practicing oncologists. Results: Topics addressed included risk of contralateral breast cancer recurrence in patients with estrogen receptor-positive early breast cancer who have undergone 5 years of adjuvant endocrine therapy, adverse events associated with endocrine therapy and their management, emergent data on adjuvant bisphosphonate therapy and its apparent benefit in reducing breast cancer recurrence, recent findings of extended adjuvant endocrine therapy trials, and the use of currently available genomic biomarker tests as a means of further informing treatment decisions. Conclusions: A summary of the discussion on these topics and several ‘expert opinion statements’ are provided herein in an effort to convey the collective insights of the panel as it relates to current standard practice

Prevention of bone metastases and management of bone health in early breast cancer

Treatment options for women with early-stage breast cancer have never been better, and the addition of bisphosphonates to adjuvant therapy is a valuable new tool capable of substantially improving clinical outcomes for these women. Several recent studies demonstrated that the anticancer activity of bisphosphonates is not limited to bone, and can translate into a reduction in disease recurrence, including reductions in locoregional and distant metastases. In addition, bisphosphonates maintain bone health during adjuvant therapy; this may be especially important for women who are at high risk for fracture

Potential antitumor effects of nitrogen-containing bisphosphonate in hormone receptor negative breast cancer patients with bone metastases

<p>Abstract</p> <p>Background</p> <p>This retrospective study evaluated, according to hormone receptor status, the antitumor effects of bisphosphonate especially on survival and disease progression in breast cancer patients with metastatic bone disease.</p> <p>Methods</p> <p>Of 317 patients with initial bone metastasis and known breast cancer subtypes, 230 patients (72.6%) had hormone receptor (HR) positive tumors, and 87 patients (27.4%) had HR negative tumors. We assessed the primary outcome of overall survival (OS), after adjusting for other factors, comparing a group that received bisphosphonates (BPs) with a group that did not receive it.</p> <p>Results</p> <p>87.8% of HR positive and 69.0% of HR negative patients received BPs with a median number of 17.7 cycles. Although BPs treatment made no survival benefit in HR positive group, HR negative patients showed a significant prolonged survival when they received BPs treatment (hazard ratio = 0.56 [95% CI 0.34 to 0.91], <it>P </it>= 0.019). In multivariate analysis, disease free interval > 2 years (<it>P </it>= 0.036), a sum of metastatic sites < 3 (<it>P </it>= 0.034), and BP treatments (<it>P </it>= 0.007) were significant factors for survival in HR negative patients.</p> <p>Conclusion</p> <p>Bisphosphonate treatment can result in a survival benefit in metastatic breast cancer patients with HR negative tumors.</p

Is risk of central nervous system (CNS) relapse related to adjuvant taxane treatment in node-positive breast cancer? Results of the CNS substudy in the intergroup phase III BIG 02-98 trial

Background: Breast cancer central nervous system (CNS) metastases are an increasingly important problem because of high CNS relapse rates in patients treated with trastuzumab and/or taxanes. Patients and methods: We evaluated data from 2887 node-positive breast cancer patients randomised in the BIG 02-98 trial comparing anthracycline-based adjuvant chemotherapy (control arms) to anthracycline-docetaxel-based sequential or concurrent chemotherapy (experimental arms). After a median follow-up of 5 years, 403 patients had died and detailed information on CNS relapse was collected for these patients. Results: CNS relapse occurred in 4.0% of control patients and 3.7% of docetaxel-treated patients. CNS relapse occurred in 27% of deceased patients in both treatment groups. CNS relapse was usually accompanied by neurologic symptoms (90%), and 25% of patients with CNS relapse died without evidence of extra-CNS relapse. Only 20% of patients survived 1 year from the diagnosis of CNS relapse. Prognosis of CNS relapse was worse for patients with meningeal carcinomatosis when compared with brain metastases. Unexpected findings included a higher rate of positive cerebrospinal fluid cytology (8% versus 3%) and more frequent use of magnetic resonance imaging for diagnosis (47% versus 30%) in the docetaxel-treated patients. Conclusion: There is no evidence that adjuvant docetaxel treatment is associated with an increased frequency of CNS relaps

Intraoperative frozen section analysis for breast-conserving therapy in 1016 patients with breast cancer

Abstract Objective: We evaluate the number of surgical two-stage procedures after FSA during breast-conserving therapy (clinical false negative result of FSA) and investigate the influence of microcalcifications, small tumour diameter, neoadjuvant therapy and preoperative biopsy on the clinical false negative rate of FSA. Subjects: We retrospectively examined 1016 patients after intraoperative FSA during breast-conserving therapy for breast cancer operated between 1995 and 2001 at the Medical University Vienna. Results: Only 9% of all patients had to undergo a two-stage operation due to a false negative intraoperative FSA result. The annual local recurrence rate was 1.2% in all patients with no difference between one-and two-stage operated patients. In situ and pT1 lesions were similarly distributed between one-stage and two-stage operated patients. The use of neoadjuvant therapy and stereotactic biopsy (reflecting non-palpable lesions and microcalcifications) were significantly predictive for a false negative FSA result. The use of a preoperative core biopsy, however, reduced the necessity of performing a two-stage operation. Conclusion: Our study demonstrates that FSA leads to a low rate of two-stage operations. Small lesions and microcalcifications as well as the occurrence of intraductal cancer cells and neoadjuvant therapy increased while preoperative core biopsy reduced the false negative rate of FSA. Overall local recurrence rates after FSA were acceptable