Comparative Study of Radial and Median Nerve Blocks with Hematoma Block under Ultrasound Guide in Distal Radius Fracture Reduction: A Randomized Clinical Trial.

Background: Distal radius fractures are one of the most common upper extremity fractures, and their incidence continues to increase due to an aging population and an increase in osteoporosis. Various methods of analgesia for distal radius fractures have been described-including hematoma blocks and nerve blocks. Hematoma blocks are a simple and effective method of providing analgesia; nonetheless, their efficacy may be limited in some cases. On the other hand, nerve blocks provide more targeted analgesia and may be more effective in reducing pain during fracture reduction. This study aimed to compare the analgesic effectiveness of radial and median nerve blocks with hematoma blocks under ultrasound guidance in treating distal radius fractures. Also, this study aimed to compare the analgesia of radial and median nerve blocks with hematoma blocks under ultrasound guidance to reduce distal radius fractures. Methods: In this prospective trial, patients with distal radius fractures referring to 2 academic centers were placed into 2 randomized groups, including hematoma block, and radial median block, both of which were ultrasound-guided. The patient's pain levels were measured and recorded based on the visual analog scale before the block, 5, 10, and 15 minutes after the block, at the start of reduction, during reduction, and 5, 10, and 15 minutes after reduction. Patient satisfaction and physician satisfaction rates were assessed, and side effects were also observed for 1 week. Quantitative variables were reported as mean ± standard deviation, and number and frequency percentages were reported for qualitative variables. The Student t test and the chi-square test were used on a case-by-case basis. The significance level was set at P ˂ 0.05. Results: In this study, 120 patients were included. The groups had no significant differences in pain reduction during the procedure. Analgesic medication was needed during the procedure for 17 patients; nerve blocks were applied for 6 patients, and hematoma blocks for 11 patients, which was statistically significant (P = 0.041). Satisfaction rates for patients and physicians performing the procedure were significantly higher in the nerve block group than in the hematoma block group ( P = 0.001; P ˂ 0.001, respectively). Conclusion: The results of this study suggest that ultrasound-guided radial and median nerve blocks can be used as alternative methods of analgesia with other techniques in the reduction of distal radius fractures in emergency departments.

Skin manifestations as potential symptoms of diffuse vascular injury in critical COVID-19 patients.

As a respiratory viral infection caused by a novel coronavirus, COVID-19 became rapidly pandemic within a few months. Despite the wide range of manifestations and organ involvement in COVID-19 patients, the exact pathogenesis of severe and fatal types of COVID-19 and causes involved with the individual base of the disease is not yet understood. Several studies have reported clinical, laboratory, and histopathological data in favor of vascular injury in multiple organs of critically ill patients with COVID-19 as a result of hyperactive immune response, inflammation, and cytokine storm. Also, both clinical and histopathological evidence points to such vascular involvements in the skin. Given the ease of clinical examinations and skin biopsy and the lower risks of transmission of COVID-19 to healthcare workers, the present review article was conducted to investigate the vascular skin manifestations of COVID-19 patients clinically and/or histopathologically as helpful clues for better understanding the pathogenesis and predicting the prognosis of the disease, especially in severe cases.

Development of central nervous system metastases as a first site of metastatic disease in breast cancer patients treated in the neoadjuvant trials GeparQuinto and GeparSixto.

BACKGROUND: The incidence of central nervous system (CNS) metastases in breast cancer patients is rising and has become a major clinical challenge. Only few data are published concerning risk factors for the development of CNS metastases as a first site of metastatic disease in breast cancer patients. Moreover, the incidence of CNS metastases after modern neoadjuvant treatment is not clear. METHODS: We analyzed clinical factors associated with the occurrence of CNS metastases as the first site of metastatic disease in breast cancer patients after neoadjuvant treatment in the trials GeparQuinto and GeparSixto (n = 3160) where patients received targeted treatment in addition to taxane and anthracycline-based chemotherapy. RESULTS: After a median follow-up of 61 months, 108 (3%) of a total of 3160 patients developed CNS metastases as the first site of recurrence and 411 (13%) patients had metastatic disease outside the CNS. Thirty-six patients (1%) developed both CNS metastases and other distant metastases as the first site of metastatic disease. Regarding subtypes of the primary tumor, 1% of luminal A-like (11/954), 2% of luminal B-like (7/381), 4% of HER2-positive (34/809), and 6% of triple-negative patients (56/1008) developed CNS metastases as the first site of metastatic disease. In multivariate analysis, risk factors for the development of CNS metastases were larger tumor size (cT3-4; HR 1.63, 95% CI 1.08-2.46, p = 0.021), node-positive disease (HR 2.57, 95% CI 1.64-4.04, p < 0.001), no pCR after neoadjuvant chemotherapy (HR 2.29, 95% CI 1.32-3.97, p = 0.003), and HER2-positive (HR 3.80, 95% CI 1.89-7.64, p < 0.001) or triple-negative subtype (HR 6.38, 95% CI 3.28-12.44, p < 0.001). CONCLUSIONS: Especially patients with HER2-positive and triple-negative tumors are at risk of developing CNS metastases despite effective systemic treatment. A better understanding of the underlying mechanisms is required in order to develop potential preventive strategies.

Evaluation of soluble carbonic anhydrase IX as predictive marker for efficacy of bevacizumab: A biomarker analysis from the geparquinto phase III neoadjuvant breast cancer trial.

We analyzed the predictive potential of pretreatment soluble carbonic anhydrase IX levels (sCAIX) for the efficacy of bevacizumab in the phase III neoadjuvant GeparQuinto trial. sCAIX was determined by enzyme-linked immunosorbent assay (ELISA). Correlations between sCAIX and pathological complete response (pCR), disease-free and overall survival (DFS, OS) were assessed with logistic and Cox proportional hazard regression models using bootstrapping for robust estimates and internal validation. 1,160 HER2-negative patient sera were analyzed, of whom 577 received bevacizumab. Patients with low pretreatment sCAIX had decreased pCR rates (12.1 vs. 20.1%, p = 0.012) and poorer DFS (adjusted 5-year DFS 71.4 vs. 80.5 months, p = 0.010) compared to patients with high sCAIX when treated with neoadjuvant chemotherapy (NCT). For patients with low sCAIX, pCR rates significantly improved upon addition of bevacizumab to NCT (12.1 vs. 20.4%; p = 0.017), which was not the case in patients with high sCAIX (20.1% for NCT vs. 17.0% for NCT-B, p = 0.913). When analyzing DFS we found that bevacizumab improved 5-year DFS for patients with low sCAIX numerically but not significantly (71.4 vs. 78.5 months; log rank 0.234). In contrast, addition of bevacizumab worsened 5-year DFS for patients with high sCAIX (81 vs. 73.6 months, log-rank 0.025). By assessing sCAIX levels we identified a patient cohort in breast cancer that is potentially undertreated with NCT alone. Bevacizumab improved pCR rates in this group, suggesting sCAIX is a predictive biomarker for bevacizumab with regards to treatment response. Our data also show that bevacizumab is not beneficial in patients with high sCAIX.

Non-sentinel axillary tumor burden applying the ACOSOG Z0011 eligibility criteria to a large routine cohort.

PURPOSE: In the ACOSOG Z0011 trial, patients with primary breast cancer (BC) and 1-2 tumor-involved sentinel lymph nodes (SLN) undergoing breast-conserving surgery gained no benefit from completing axillary lymph node dissection (cALND). This paper reports cALND rates performed in clinical routine on patients who would meet the Z0011 criteria. Further, patients still received cALND were analyzed concerning the number of non-sentinel metastases (NSM) to estimate occult axillary tumor burden. METHODS: Data were retrospectively analyzed from patients treated in 179 German breast centers between 2008 and 2015. Time-trend rates were determined for cALND regarding the presence of axillary macrometastases or micrometastases. Descriptive statistics were used to report the number of NSM depending on the number of SLN removed, tumor-involved SLN, tumor stage (pT1-2), and immunohistochemical subtype. Factors associated with NSM were identified using multivariable logistic regression. RESULTS: Altogether, data for 188,909 patients were available, of whom 13,741 (7.3%) were identified eligible for the Z0011 criteria. For these patients, the cALND rate for macrometastases declined from 96.4% in 2008 to 49.7% in 2015, for micrometastases from 86.7 to 5.9%. In total 9773 patients still received cALND, 33.4% of whom had NSM. The NSM rates were: 38.8% for pN(1/1sn), 28.6% for pN(1/2sn), and 50.9% for pN(2/2sn). Hormone receptor (HR) positive/HER2+ showed the highest NSM rate (41.6%), HR-/HER2- the lowest rate (29.4%). CONCLUSIONS: The rate of cALND for ACOSOG Z0011 eligible patients has decreased substantially in routine care in our nationwide cohort. Our data reveal a relatively high prevalence of additional axillary NSM tumor burden.

Which patients with sentinel node-positive breast cancer after breast conservation still receive completion axillary lymph node dissection in routine clinical practice?

PURPOSE: In the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial, patients with 1 or 2 tumour-involved sentinel lymph nodes (SLNs) gained no benefit from completion axillary lymph dissection (cALND). We examined implementation of evidence from this trial into routine clinical management. METHODS: Data were included from patients diagnosed with primary breast cancer in German breast cancer units between 2008 and 2015 and analysed retrospectively from a prospective maintained database. Descriptive analyses assessed time-trend changes in axillary surgery. Factors associated with cALND in patients with 1 or 2 positive SLNs were identified using multivariable logistic regression analysis. RESULTS: Overall, 179 breast cancer units provided data for 188,909 patients, of whom 13,741 (7.3%) had pT1/2cN0M0 invasive breast cancer with 1 or 2 tumour-involved SLNs and underwent breast-conserving surgery and adjuvant radiotherapy. cALND use decreased from 94.6% in 2008 to 46.9% in 2015 (p < 0.001). In multivariable analyses, the following factors were associated with cALND: fewer removed SLNs; two tumour-affected SLNs; younger age; lower annual case volume per hospital; higher tumour grade and lymphovascular invasion. No statistically significant influence was detected for hormone receptor or HER2 status. CONCLUSION: In our cohort, 7.3% of patients with primary breast cancer met the ACOSOG Z0011 inclusion criteria and could potentially have been spared the morbidity of cALND. cALND tended to be performed in patients with a higher axillary tumour burden. This study shows a shift towards less extensive axillary surgery through rapid implementation of new clinical trial evidence into routine clinical practice.

Evolution of the Use of Completion Axillary Lymph Node Dissection in Patients with T1/2N0M0 Breast Cancer and Tumour-Involved Sentinel Lymph Nodes Undergoing Mastectomy: A Cohort Study.

BACKGROUND: In breast cancer, completion axillary lymph node dissection (cALND) was previously recommended for patients with at least one tumour-affected sentinel lymph node (SLN). Several prospective trials predominantly in patients undergoing breast-conserving surgery showed no benefit and increased arm morbidity with this procedure. We report the influence of these trials on clinical practice of patients undergoing mastectomy. METHODS: We analysed prospectively collected data from patients with primary invasive breast cancer treated at German breast cancer units between January 2008 and December 2015. Time trends of cALND rates were analysed in patients undergoing mastectomy for T1/2N0M0 breast cancer with one or two tumour-involved SLNs. Multivariable logistic regression was used to determine factors influencing the decision not to perform cALND. RESULTS: Among the entire study cohort of 166,074 patients treated at 179 breast cancer units, 4093 patients (2%) had T1/2N0M0 breast cancer with one or two tumour-involved SLNs and underwent mastectomy. cALND rates decreased from 89.9% in 2010 to 55.5% in 2015 (p < 0.001). Rates decreased from 82% to 8% in patients with micrometastatic SLN disease and from 93% to 63% in those with macrometastasis (p < 0.001). In multivariable analysis, factors associated with omission of cALND were treatment at a general, nonacademic hospital, pT1 status, older age, higher number of removed SLNs, fewer tumour-affected SLNs, and SLN micrometastasis (all p < 0.001). CONCLUSIONS: Despite limited evidence from prospective trials relating to the omission of cALND specifically in patients undergoing mastectomy, our nationwide data show that use of cALND decreased in these patients in routine clinical practice.

Influence of patient and tumor characteristics on therapy persistence with letrozole in postmenopausal women with advanced breast cancer: results of the prospective observational EvAluate-TM study.

BACKGROUND: Treatment of postmenopausal, hormone receptor-positive metastatic breast cancer (MBC) patients varies despite clear therapy guidelines, favoring endocrine treatment (ET). Aim of this study was to analyze persistence of palliative aromatase inhibitor (AI) monotherapy in MBC patients. METHODS: EvAluate-TM is a prospective, multicenter, noninterventional study to evaluate treatment with letrozole in postmenopausal women with hormone receptor-positive breast cancer. To assess therapy persistence, defined as the time from therapy start to the end of the therapy (TTEOT), two pre-specified study visits took place after 6 and 12 months. Competing risk survival analyses were performed to identify patient and tumor characteristics that predict TTEOT. RESULTS: Out of 200 patients, 66 patients terminated treatment prematurely, 26 (13%) of them due to causes other than disease progression. Persistence rate for reasons other than progression at 12 months was 77.7%. Persistence was lower in patients who reported any adverse event (AE) in the first 30 days of ET (89.5% with no AE and 56% with AE). Furthermore, patients had a lower persistence if they reported compliance problems in the past before letrozole treatment. CONCLUSIONS: Despite suffering from a life-threatening disease, AEs of an AI will result in a relevant number of treatment terminations that are not related to progression. Some subgroups of patients have very low persistence rates. Especially with regard to novel endocrine combination therapies, these data imply that some groups of patients will need special attention to guide them through the therapy process. TRIAL REGISTRATION: Clinical Trials Number: CFEM345DDE19.

Clinical relevance and concordance of HER2 status in local and central testing-an analysis of 1581 HER2-positive breast carcinomas over 12 years.

Human epidermal growth factor receptor 2 (HER2) is a central predictive biomarker in breast cancer. Inaccurate HER2 results in different laboratories could be as high as 20%. However, this statement is based on data generated more than 13 years ago and may not reflect the standards of modern diagnostic pathology. We compared central and local HER2 testing in a total of 1581 HER2-positive tumors from five clinical trials. We evaluated the clinical relevance for pathological complete response (pCR) and disease-free survival in a subgroup of 677 tumors, which received an anti-HER2 therapy. Over the period of 12 years, the discordance rate for HER2 decreased from 52.4 (GeparTrio) to 8.4% (GeparSepto). Discordance rates were significantly higher in hormone receptor (HR)-positive tumors (26.6%), compared to HR-negative tumors (16.3%, P<0.0001), which could be explained by a different distribution of HER2 mRNA levels in HR-positive and HR-negative tumors. pCR rates were significantly lower in discordant tumors (13.7%) compared to concordant tumors (32.2%, GeparQuattro and GeparQuinto, P<0.001). In survival analysis, tumors with discordant HER2 testing had a reduced overall survival (OS) in the HR-negative group (P=0.019) and a trend for improved OS in the HR-positive group (P=0.125). The performance of local HER2 testing was considerably improved over time and has reached a 92% concordance, which shows that quality initiatives in diagnostic pathology are working. Tumors with discordant HER2 testing had a reduced therapy response and different survival rates.

Can low-dose of ketamine reduce the need for morphine in renal colic? A double-blind randomized clinical trial.

BACKGROUND: The combination of morphine with low doses of ketamine (MK) has been utilized in the Emergency Department (ED) compared with morphine and placebo (MP) for the treatment of acute pain in few studies. The purpose of this study was to compare the effect of MP with MK for the treatment of severe pain with renal colic of patients who had been referred to the ED. METHODS: This study is a double blind randomized clinical trial on patients with severe renal colic pain who were referred to the ED. Patients were enrolled with pain severity of at least 6 of the 10 visual analogue scales (VAS). Patients were divided into two groups: Morphine 0.1mg/kg and placebo (MP group) and morphine 0.1mg/kg and ketamine 0.15mg/kg (MK group). Pain of patients was studied in 10, 30, 60, 90, and 120min after injection. RESULTS: Totally, 106 patients were enrolled in study groups. Assessment of the average pain during 120min at 10 and 30min after the start in the drug, MK group was significantly lower than the MP group (p=0.019 and p=0.003 respectively). CONCLUSION: Given that combinations of morphine with low doses of ketamine in patients with renal colic pain causes more pain and morphine consumption reduction then this combination is suggested as an alternative treatment that could be utilized in patients with renal colic.

Effectiveness of an interprofessional education model based on the transtheoretical model of behaviour change to improve interprofessional collaboration.

This study aimed to assess the effectiveness of an interprofessional education model (IPE) based on the transtheoretical model to improve the participants' interprofessional collaborative practice. The study was conducted in Iran using a controlled before-and-after study design. The participants (n = 91) were the residents of emergency medicine and nurses of the emergency units from two teaching hospitals affiliated to Iran University of Medical Sciences. The participants in the intervention group (n = 40) were 22 residents and 18 nurses. The control group (n = 51) consisted of 20 residents and 31 nurses. The participants were classified based on their stage of readiness to change. The interventions were two-day workshops for each stage (i.e., attitude and intention). We used the Interprofessional Collaborator Assessment Rubric (ICAR) to assess the effectiveness of the developed model. The interprofessional collaboration of the participants in the intervention and control groups was assessed at four time points before and after the intervention in the real emergency unit environment. Student's t-test and repeated measures analysis of variance (RM-ANOVA) were used to analyse the data. We used partial eta-squared (η2) for effect size calculations. The mean values of ICAR scores in the intervention and control groups were 95.63 ± 19.14 and 89.19 ± 16.11 before the intervention. The mean values of ICAR scores at 3 months after the intervention were 99.82 ± 22.32 and 88.29 ± 16.87 in the intervention and control groups, respectively. After 6 months, the mean values of ICAR scores of the intervention and control groups were 98.6 ± 23.40 and 87.98 ± 16.01, respectively. The results showed that the intervention had a medium educational effect size (partial η2 = 0.06) on performance of the participants. Our results showed that an IPE model that is tailored to the learners' stage of readiness to change improves interprofessional collaboration in the participants. The developed model could be applied for improving interprofessional collaborative performance in other IPE programmes.

Detection of circulating tumor cells using manually performed immunocytochemistry (MICC) does not correlate with outcome in patients with early breast cancer - Results of the German SUCCESS-A- trial.

BACKGROUND: Recently, the prognostic significance of circulating tumor cells (CTCs) in primary breast cancer as assessed using the Food-and-Drug-Administration-approved CellSearch® system has been demonstrated. Here, we evaluated the prognostic relevance of CTCs, as determined using manually performed immunocytochemistry (MICC) in peripheral blood at primary diagnosis, in patients from the prospectively randomized multicenter SUCCESS-A trial (EudraCT2005000490-21). METHODS: We analyzed 23 ml of blood from 1221 patients with node-positive or high risk node-negative breast cancer before adjuvant taxane-based chemotherapy. Cells were separated using a density gradient followed by epithelial cell labeling with the anti-cytokeratin-antibody A45-B/B3, immunohistochemical staining with new fuchsin, and cytospin preparation. All cytospins were screened for CTCs, and the cutoff for positivity was at least one CTC. The prognostic value of CTCs with regard to disease-free survival (DFS), distant disease-free survival (DDFS), breast-cancer-specific survival (BCSS), and overall survival (OS) was assessed using both univariate analyses applying the Kaplan-Meier method and log-rank tests, and using multivariate Cox regressions adjusted for other predictive factors. RESULTS: In 20.6 % of all patients (n = 251) a median of 1 (range, 1-256) CTC was detected, while 79.4 % of the patients (n = 970) were negative for CTCs before adjuvant chemotherapy. A pT1 tumor was present in 40.0 % of patients, 4.8 % had G1 grading and 34.6 % were node-negative. There was no association between CTC positivity and tumor stage, nodal status, grading, histological type, hormone receptor status, Her2 status, menopausal status or treatment. Univariate survival analyses based on a median follow-up of 64 months revealed no significant differences between CTC-positive and CTC-negative patients with regard to DFS, DDFS, BCSS, or OS. This was confirmed by fully adjusted multivariate Cox regressions, showing that the presence of CTCs (yes/no) as assessed by MICC did not predict DFS, DDFS, BCSS or OS. CONCLUSIONS: We could not demonstrate prognostic relevance regarding CTCs that were quantified using the MICC method at the time of primary diagnosis in our cohort of early breast cancer patients. Further studies are necessary to evaluate if the presence of CTCs assessed using MICC has prognostic relevance, or can be used for risk stratification and treatment monitoring in adjuvant breast cancer. TRIAL REGISTRATION: The ClinicalTrial.gov registration ID of this prospectively randomized trial is NCT02181101 ; the (retrospective) registration date was June 2014 (study start date September 2005).

Can intravenous acetaminophen reduce the needs to more opioids to control pain in intubated patients?

AIMS: To evaluate the effect of intravenous (IV) acetaminophen on reducing the need for morphine sulfate in intubated patients admitted to the Intensive Care Unit (ICU). SETTINGS AND DESIGN: Current study was done as a clinical trial on the patients supported by mechanical ventilator. SUBJECTS AND METHODS: Behavioral pain scale (BPS) scoring system was used to measure pain in the patients. All of the patients received 1 g, IV acetaminophen, every 6 h during the 1(st) and 3(rd) days of admission and placebo during the 2(nd) and 4(th) days. Total dose of morphine sulfate needed, its complications, and the BPS scores at the end of every 6 h interval were compared. RESULTS: Totally forty patients were enrolled. The mean pain scores were significantly lower in the 2(nd) and 4(th) days (4.33 and 3.66, respectively; mean: 4.0) in which the patients had received just morphine sulfate compared to the 1(st) and 3(rd) days (7.36 and 3.93, respectively; mean: 5.65) in which the patients had received acetaminophen in addition to morphine sulfate too (P < 0.001). Cumulative dose of morphine sulfate used, was significantly higher in the 1(st) and 3(rd) days (8.92 and 3.15 mg, respectively; 12.07 mg in total) compared to the 2(nd) and 4(th) days (6.47 mg and 3.22 mg, respectively; 9.7 mg in total) (P = 0.035). CONCLUSION: In our study, IV acetaminophen had no effect on decreasing the BPSs and need of morphine sulfate in intubated patients admitted to ICU.

Genetic variants in VEGF pathway genes in neoadjuvant breast cancer patients receiving bevacizumab: Results from the randomized phase III GeparQuinto study.

Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression-free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2-negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre-planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF-A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49-3.75), 1.20 (95% CI, 0.88-1.64) and 0.61 (95% CI, 0.34-1.12). Notably, some SNPs in VEGF-A exhibited a more pronounced effect in the triple-negative subgroup. Several SNPs in VEGF-A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers.

Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer.

BACKGROUND: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor A, has shown clinical efficacy in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. We evaluated the efficacy, measured according to the rate of pathological complete response (absence of invasive and intraductal disease in the breast and the axillary lymph nodes), and the safety of adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage breast cancer. METHODS: We randomly assigned 1948 patients with a median tumor size of 40 mm on palpation to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel, with or without concomitant bevacizumab. Patients with untreated HER2-negative breast cancer were eligible if they had large tumors, hormone-receptor-negative disease, or hormone-receptor-positive disease with palpable nodes or positive findings on sentinel-node biopsy, and no increased cardiovascular or bleeding risk. RESULTS: Overall, the rates of pathological complete response were 14.9% with epirubicin and cyclophosphamide followed by docetaxel and 18.4% with epirubicin and cyclophosphamide followed by docetaxel plus bevacizumab (odds ratio with addition of bevacizumab, 1.29; 95% confidence interval, 1.02 to 1.65; P=0.04); the corresponding rates of pathological complete response were 27.9% and 39.3% among 663 patients with triple-negative tumors (P=0.003) and 7.8% and 7.7% among 1262 patients with hormone-receptor-positive tumors (P=1.00). Breast-conserving surgery was possible in 66.6% of the patients in both groups. The addition of bevacizumab, as compared with neoadjuvant therapy alone, was associated with a higher incidence of grade 3 or 4 toxic effects (febrile neutropenia, mucositis, the hand-foot syndrome, infection, and hypertension) but with a similar incidence of surgical complications. CONCLUSIONS: The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response among patients with HER2-negative early-stage breast cancer. Efficacy was restricted primarily to patients with triple-negative tumors, in whom the pathological complete response is considered to be a reliable predictor of long-term outcome. (Funded by Sanofi-Aventis and Roche, Germany; ClinicalTrials.gov number, NCT00567554.).

Systematization of Oncoplastic Surgery: Selection of Surgical Techniques and Patient-Reported Outcome in a Cohort of 1,035 Patients.

INTRODUCTION: Functional and aesthetic outcome after breast-conserving surgery are vital endpoints for patients with primary breast cancer. A large variety of oncoplastic techniques exist; however, it remains unclear which techniques yield the highest rates of local control at first surgery, omission of reexcision or subsequent mastectomy, and merits the highest degree of patient satisfaction. METHODS: In this retrospective case cohort trial with a customized investigational questionnaire for assessment of patient satisfaction with the surgical result, we analyzed 1,035 patients with primary, unilateral breast cancer and oncoplastic surgery from 2004 to 2009. RESULTS: Analysis of patient reported outcome (PRO) revealed that 88 % of the cohort was satisfied with their aesthetic result using oncoplastic techniques following the concept presented. These results also were achieved in difficult tumor localizations, such as upper inner and lower inner quadrant. Conversion rate from breast-conserving therapy to secondary mastectomy was low at 7.2 % (n = 68/944 patients). The systematization of oncoplastic techniques presented-embedded in a multimodal concept of breast cancer therapy-facilitates tumor control with a few number of uncomplicated techniques adapted to tumor site and size with a median resection of 32 (range 11-793) g. Five-year recurrence rate in our cohort was 4.0 %. CONCLUSIONS: Patient's satisfaction was independent from age, body mass index, resection volume, tumor localization, and type of oncoplastic surgery (p > 0.05). We identified postoperative pain as an important negative impact factor on patient's satisfaction with the aesthetic result (p = 0.0001).

Impact of multifocal or multicentric disease on surgery and locoregional, distant and overall survival of 6,134 breast cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: The impact of tumor focality on type of surgery, local recurrence rate, and survival after neoadjuvant chemotherapy (NACT) for breast cancer is not fully understood. This study aimed to compare local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS) according to focality stratified by type of surgery and pathologic complete response (pCR), with a focus on breast conservation. METHODS: Participants (n = 6,134) in the GeparTrio, GeparQuattro, and GeparQuinto trials with operable or locally advanced tumors receiving NACT were classified as having unifocal (1 lesion), multifocal (≥ 2 lesions in 1 quadrant), or multicentric (≥ 1 lesion in ≥ 2 quadrants) disease. The study investigated LRFS, DFS, and OS according to focality stratified by type of surgery and pathologic complete response. RESULTS: The patients were classified as having unifocal (n = 4,733, 77.1 %), multifocal (n = 820, 13.4 %), or multicentric (n = 581, 9.5 %) tumors. The respective pCR rates were 19.4, 16.5, and 14.4 %. Breast conservation was performed for 71.6, 58.5, and 30 % of these patients, respectively (P < 0.001). The LRFS rate was 92.9 % for the unifocal, 95.1 % for the multifocal, and 90.4 % for the multicentric tumors (P = 0.002). The patients with multicentric tumors but not the patients with multifocal tumors had worse DFS (P < 0.001) and OS (P = 0.009) than the patients with unifocal tumors. However, LRFS, DFS, and OS were not inferior for the patients with multicentric or multifocal tumors if pCR was achieved or breast conservation was performed after NACT. CONCLUSION: Breast conservation is feasible for clinically multifocal or multicentric breast cancer patients who undergo NACT without worsening LRFS if tumor-free margins can be attained or if patients achieve a pCR.

Favorable results after conservative management of 316 valproate intoxicated patients.

BACKGROUND: Valproic acid (VPA) is an effective antiepileptic drug widely used worldwide. Despite several studies indicating the usefulness of intravenous L-carnitine in the treatment of VPA poisoning, this drug is not readily available in Iran. The aim of this study was to determine whether supportive care without antidote would result in acceptable outcomes in VPA poisoned patients. MATERIALS AND METHODS: In an observational, retrospective, single-center case series, all patients >12-year-old with VPA overdose who had referred to a tertiary center between 2009 and 2013 were consecutively enrolled. Patients' demographic and presenting features, physical examinations, clinical management, laboratory data, and outcomes were recorded. RESULTS: A total of 316 patients were enrolled with pure VPA toxicity. The most common presenting signs/symptoms were drowsiness, nausea and vomiting, vertigo, and headache. In the course of the disease, 14 patients (4.4%) were intubated and three (0.9%) required hemodialysis with mean dialysis sessions of two. Fourteen patients were admitted to Intensive Care Unit, and seizures occurred in five. The initial level of consciousness was lower in patients with poor outcome. The median ingested dose of VPA in patients who required dialysis was significantly higher (20 vs. 6 g; P = 0.006). Multivariate analyses revealed that coma on presentation was associated with a worse outcome (P = 0.001; odds ratio = 61.5, 95% CI = 5.8-646.7). CONCLUSION: Prognosis of VPA poisoned patients appears to be good even with supportive care. According to our study, older age, ingestion of higher amounts of VPA and lower PCO2, HCO3, base excess, and CPK levels prone the patients to more severe toxicities in univariate analysis, but the main poor prognostic factor is coma on presentation in multivariate analysis.

Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial.

BACKGROUND: Preclinical data suggest that triple-negative breast cancers are sensitive to interstrand crosslinking agents, and that synergy may exist for the combination of a taxane, trastuzumab, and a platinum salt for HER2-positive breast cancer. We therefore aimed to assess the efficacy of the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive breast cancer. METHODS: Patients with previously untreated, non-metastatic, stage II-III, triple-negative breast cancer and HER2-positive breast cancer were enrolled. Patients were treated for 18 weeks with paclitaxel (80 mg/m(2) once a week) and non-pegylated liposomal doxorubicin (20 mg/m(2) once a week). Patients with triple-negative breast cancer received simultaneous bevacizumab (15 mg/kg intravenously every 3 weeks). Patients with HER2-positive disease received simultaneous trastuzumab (8 mg/kg initial dose with subsequent doses of 6 mg/kg intravenously every 3 weeks) and lapatinib (750 mg daily). Patients were randomly assigned in a 1:1 ratio with dynamic allocation and minimisation, stratified by biological subtype and Ki-67 level to receive, at the same time as the backbone regimens, either carboplatin (AUC 1·5 [2·0 for the first 329 patients] once a week) or no carboplatin. The primary endpoint the proportion of patients who achieved a pathological complete response (defined as ypT0 ypN0), analysed for all patients who started treatment; a p value of less than 0·2 was deemed significant for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01426880. FINDINGS: 296 patients were randomly assigned to receive carboplatin and 299 to no additional carboplatin, of whom 295 and 293 started treatment, respectively. In this final analysis, 129 patients (43·7%, 95% CI 38·1-49·4) in the carboplatin group achieved a pathological complete response, compared with 108 patients (36·9%, 31·3-42·4) without carboplatin (odds ratio 1·33, 95% CI 0·96-1·85; p=0·107). Of the patients with triple-negative breast cancer, 84 (53·2%, 54·4-60·9) of 158 patients achieved a pathological complete response with carboplatin, compared with 58 (36·9%, 29·4-44·5) of 157 without (p=0·005). Of the patients with HER2-positive tumours, 45 (32·8%, 25·0-40·7) of 137 patients achieved a pathological complete response with carboplatin compared with 50 (36·8%, 28·7-44·9) of 136 without (p=0·581; test for interaction p=0·015). Haematological and non-haematological toxic effects that were significantly more common in the carboplatin group than in the no-carboplatin group included grade 3 or 4 neutropenia (192 [65%] vs 79 [27%]), grade 3 or 4 anaemia (45 [15%] vs one [<1%]), grade 3 or 4 thrombocytopenia (42 [14%] vs one [<1%]), and grade 3 or 4 diarrhoea (51 [17%] vs 32 [11%]); carboplatin was more often associated with dose discontinuations (141 [48%] with carboplatin and 114 [39%] without carboplatin; p=0·031). The frequency of grade 3 or 4 haematological events decreased from 82% (n=135) to 70% (n=92) and grade 3 or 4 non-haematological events from 78% (n=128) to 59% (n=77) in the carboplatin arm when the dose of carboplatin was reduced from AUC 2·0 to 1·5. INTERPRETATION: The addition of neoadjuvant carboplatin to a regimen of a taxane, an anthracycline, and targeted therapy significantly increases the proportion of patients achieving a pathological complete response. This regimen seems to increase responses in patients with triple-negative breast cancer, but not in those with HER2-positive breast cancer. FUNDING: GlaxoSmithKline, Roche, and Teva.

Surgical outcome after neoadjuvant chemotherapy and bevacizumab: results from the GeparQuinto study (GBG 44).

PURPOSE: Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, has shown increased pathological complete response rates when added to neoadjuvant chemotherapy. In various cancer types, bevacizumab treatment was accompanied by an increased risk of bleedings and other surgical complications. We assessed associated surgical complications. METHODS: In the GeparQuinto trial, 1,948 patients were randomized to receive four cycles epirubicin/cyclophosphamide (EC, 90/600 mg/m(2) q3w) followed by four cycles docetaxel (D, 100 mg/m(2) q3w) each with (ECB-DB) or without (EC-D) bevacizumab (B, 15 mg/kg q3w) concurrent with chemotherapy. Surgery had to be performed not earlier than 28 days after the last bevacizumab infusion, but within days 21 and 35 after the last chemotherapy. RESULTS: In 743 (38.1 %) patients, a surgical complication (bleedings, hematomas, necrosis, wound infections, abscess) was documented prospectively. Baseline characteristics of the patients were well balanced between both arms. The breast-conserving surgery (BCS) rate (N = 502) was 69.1 % (EC-D) and 71.9 % (ECB-DB; p = 0.464). The first surgical procedure was performed at a median of 29 (EC-D) and 34 days (ECB-DB) after last chemotherapy with or without bevacizumab infusion (p < 0.001). Surgical complications were documented in 38 (10.9 %; EC-D) and 59 (15.0 %; ECB-DB) patients (p = 0.103). Surgical complications were significantly higher after ECD-DB only in patients treated with BCS (N = 53; p = 0.029) or in those requiring repeat surgery in order achieve clear margins (N = 23; p = 0.037) compared to the EC-D group. CONCLUSIONS: Addition of bevacizumab to neoadjuvant chemotherapy might be associated with an increased risk for surgical complications in patients treated with BCS or after repeated surgeries.