Systematic review of lymphovenous anastomosis (LVA) for the treatment of lymphedema.

INTRODUCTION: Lymphedema is a chronic condition caused by the obstruction or impairment of lymphatic fluid transport resulting in irreversible skin fibrosis. Besides conservative therapy, surgical techniques for lymphedema including liposuction, lymphatico-lymphatic bypass, lymphovenous anastomosis (LVA), and vascularized lymph node transfer (VLNT) are options with increasing popularity in the recent past. In our review, we investigated the efficacy of LVA for the treatment of lymphedema. Both objective and subjective outcomes of surgical treatment were evaluated. METHODS: Studies were identified through systematic review in PubMed database up to September 2016. Only original Articles which exclusively performed LVA for lymphedema treatment were included. Our primary endpoint was the objective of a subjective postoperative lymphedema reduction. RESULTS: A total of 293 titles were identified, out of which 18 studies including 939 patients were deemed eligible. The studies included in this review describe significant variations in surgical techniques, number of anastomoses and supplementary interventions. All studies reported objective reductions in circumference measurements. Subjective symptom relief was found in 50-100% of the patients as well as a reduction in the number of cellulitis episodes in all investigated cases. CONCLUSION: Although the studies included in this review showed great heterogeneity, LVA surgery revealed both objective and subjective improvements in most patients.

Physical activity and survival of postmenopausal, hormone receptor-positive breast cancer patients: results of the Tamoxifen Exemestane Adjuvant Multicenter Lifestyle study.

BACKGROUND: Physical activity has been related to improved breast cancer outcomes. Especially in the older breast cancer population, physical activity may be important because old age is associated with comorbidities and decreased physical function. The purpose of this study was to investigate the relation between physical activity and overall survival, breast cancer-specific survival, and recurrence in several age groups of postmenopausal breast cancer patients. METHODS: The Tamoxifen Exemestane Adjuvant Multinational Lifestyle study was a side study of the Tamoxifen Exemestane Adjuvant Multinational trial and prospectively investigated lifestyle habits of postmenopausal, hormone receptor-positive breast cancer patients. The relations between prediagnosis and postdiagnosis physical activity and overall survival, breast cancer-specific survival, and recurrence-free survival were assessed with Cox regression and competing risk regression models. RESULTS: Among 521 patients, high levels of physical activity before and after the diagnosis were associated with better overall survival (the multivariate hazard ratios were 0.50 [95% confidence interval = 0.26-0.98] and 0.57 (95% confidence interval = 0.26-1.40] for patients who were very active before and after the diagnosis, respectively, in comparison with inactive patients). This was most evident in patients who were 65 years old or older. Physical activity was not significantly associated with breast cancer-specific survival or the relapse-free period. CONCLUSIONS: Overall survival was better for patients who were active before and after the diagnosis. In contrast with previous studies, breast cancer survival and the risk of recurrence were not significantly associated with physical activity. These findings confirmed the need for more studies investigating the use of physical activity to supplement breast cancer treatment in older patients.

Germline variants in the CYP19A1 gene are related to specific adverse events in aromatase inhibitor users: a substudy of Dutch patients in the TEAM trial.

Musculoskeletal adverse events (MSAEs) and vasomotor symptoms (VMSs) are known side-effects of aromatase inhibitors, and may be related to genetic variations of the aromatase gene (CYP19A1). We investigated the relationship between these specific AEs and single nucleotide polymorphisms (SNPs) in the CYP19A1 gene in postmenopausal, hormone receptor-positive early breast cancer (BC) patients treated with adjuvant exemestane for 5 years. Dutch patients who were randomized to receive 5 years of exemestane in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial were included. A tagging-SNP approach was performed, covering 80 % of variations of the CYP19A1 gene with 30 SNPs. Logistic regression analyses were used to assess the risk of reporting VMSs or MSAEs in relation to genotypes within selected SNPs. Of 737 included patients, 281 patients reported at least one MSAE (n = 210) or VMS (n = 163). Homozygous AA genotype of rs934635 was associated with a significantly higher odds of MSAEs (multivariate odds ratio (OR) 4.66, p = 0.008) and VMSs (multivariate OR 2.78, p = 0.044). Regarding both rs1694189 and rs7176005, the homozygous variant genotypes (TT) were associated with a higher odds of VMSs, but not MSAEs (OR 1.758, p = 0.025 and OR 6.361, p = 0.021, respectively). Our exploratory analysis demonstrated that some CYP19A1 gene variations may be associated with MSAEs and/or VMSs. Specifically, patients with the homozygous variant rs934635 genotype reported more MSAEs and VMSs. Although further confirmatory studies are warranted, genomic profiling can help identify patients at an increased risk of reporting these specific AEs, potentiating further personalized BC treatment.

Investigating group A Streptococcus antibiotic tolerance in necrotizing fasciitis.

Group A Streptococcus (GAS) necrotizing fasciitis (NF) is a difficult-to-treat bacterial infection associated with high morbidity and mortality despite extensive surgery and targeted antibiotic treatment. Difficult-to-treat infections are often characterized by the presence of bacteria surviving prolonged antibiotic exposure without displaying genetic resistance, referred to as persisters. In the present study, we investigated the presence of GAS persisters in tissue freshly debrided from patients as well as in an in vivo mouse model of NF and examined the phenomenon of antibiotic tolerance. Time-lapse imaging of GAS plated directly upon isolation from NF debrided tissue and an antibiotic challenge-based persisters assay were used to assess the presence of persisters. We show for the first time that GAS recovered directly from freshly debrided NF tissue is characterized by heterogeneous and overall delayed colony appearance time, suggesting the presence of persisters. Acidic pH or nutrient stress exposure, mimicking the NF-like environment in vitro, led to a similar phenotypic heterogeneity and resulted in enhanced survival upon antibiotic challenge, confirming the presence of GAS persisters. GAS persisters might contribute to NF treatment failure, despite extensive surgery and adequate antibiotic treatment.IMPORTANCEDifficult-to-treat and recurrent infections are a global problem burdening society and the health care system alike. Unraveling the mechanisms by which bacteria can survive antibiotic treatment without developing genetic resistance is of utmost importance to lay the foundation for new, effective therapeutic approaches. For the first time, we describe the phenomenon of antibiotic tolerance in group A Streptococcus (GAS) isolated from necrotizing fasciitis (NF) patients. Dormant, non-replicating cells (persisters) are tolerant to antibiotics and their occurrence in vivo is reported in an increasing number of bacterial species. Tailored treatment options, including the use of persisters-targeting drugs, need to be developed to specifically target dormant bacteria causing difficult-to-treat and recurrent infections.

Efficacy of closed reduction of nasal fractures-a retrospective analysis with focus on factors affecting functional and aesthetic outcomes.

BACKGROUND: Nasal bone fractures are the most common type of facial bone fractures. While the nasal anatomy and closed reduction techniques of nasal fractures are well described, there is a paucity of data reporting on the need for revision rhinoplasty. The objective of this study is to analyze the factors affecting the outcome and need for revision rhinoplasty in patients who underwent closed reduction for nasal bone fracture. METHODS: From 2010 to 2020, a total of 417 consecutive patients underwent closed nasal reduction. Medical files of the patients were reviewed retrospectively. The rate of rhinoplasty after fracture consolidation was determined. Factors influencing the need for revision rhinoplasty were assessed using univariable and multivariable logistic regression analyses. RESULTS: Forty-seven patients (11.3%) required revision rhinoplasty after fracture healing. Patients who had suffered an additional septum fracture were more likely to undergo rhinoplasty. The risk of the need for open revision rhinoplasty after fracture healing was increased for patients complaining of airway obstruction at the time of cast removal after closed reduction. CONCLUSION: A certain number of patients will require secondary revision rhinoplasty after closed reduction of a nasal fracture. Subjective airway obstruction at the time of cast removal after closed reduction is a predictor for revision rhinoplasty. Prospective studies are required to support the findings of this investigation.

Patient-Reported Outcomes in Free-Flap Breast Reconstructive Surgery over Time (PRO-BREST).

Introduction: Patient-reported outcomes (PROMs) are increasingly relevant to assess surgical quality and guide decisions in breast reconstruction (BR). Satisfaction with outcomes may change as time progresses. We assessed satisfaction in patients who underwent free-flap BR in the last 12 years. Methods: All patients who underwent free-flap BR from 2006 to 2018 were invited to complete the validated BREAST-Q for reconstruction. The BREAST-Q comprises 6 domains covering various aspects of satisfaction. Unadjusted linear regression assessed the relationship between different domains of the BREAST-Q and time since BR. Two-sample t tests assessed differences in satisfaction between patients who underwent BR ≥5 years versus <5 years prior. Results: Forty-three women with primary or secondary free-flap BR between 2006 and 2018 were included in the study. Most patients (n = 33, 76.7%) underwent DIEP flap BR. Overall satisfaction with breasts and with outcomes improved as time since BR increased (p = 0.031 and p = 0.017, respectively). Overall satisfaction with outcomes scored higher in patients with BR ≥5 years prior (≥5 years vs. <5 years: breast score 88.6 (SD 12.5) versus 66.9 (SD 21.8); p = 0.005). Satisfaction with breasts and psychosocial well-being also scored higher in these patients. There was no difference in results between primary and secondary BR. Patients who underwent additional surgery (refinements) reported higher satisfaction with outcomes and abdominal well-being. Conclusions: PROMs concerning satisfaction with breast and with outcomes following BR improve as time since treatment progresses. This study demonstrates that time since diagnosis may be an important factor in satisfaction. It underlines the importance of long-term PROMs related to BR, to help provide patients and health care professionals in decision-making and in managing expectations related to BR.

Efficacy of six month neoadjuvant endocrine therapy in postmenopausal, hormone receptor-positive breast cancer patients--a phase II trial.

BACKGROUND: Neoadjuvant hormonal therapy (NHT) is playing an increasing role in the clinical management of breast cancer (BC) and may improve surgical outcomes for postmenopausal, oestrogen receptor (ER)-positive BC patients. However, there is currently no consensus on the optimal duration of NHT before surgery. Here, we present the outcomes of the TEAM IIA trial, a multicentre, phase II trial investigating the efficacy of six months of neoadjuvant exemestane in postmenopausal, strong ER-positive (ER+, ⩾50%) BC patients. METHODS: 102 patients (stage T2-T4ac) were included in the study after exclusion of ineligible patients. Primary end-point was clinical response at 3 and 6 months as measured by palpation. Secondary end-point was radiological response as measured by magnetic resonance imaging (MRI), mammography and/or ultrasound. Linear mixed models (95% confidence interval (CI)) were used to compare changes in mean tumour size (in mm) between baseline, 3 and 6 months after the start of endocrine therapy. Conversion rates from mastectomy to breast conserving surgery (BCS) were evaluated. RESULTS: Median age of all patients was 72 years (range 53-88). Overall response rate by clinical palpation was 64.5% in all patients with a final palpation measurement. Four patients had clinically progressive disease. 63 patients had both 3-month and >3-month palpation measurements. Overall response was 58.7% at 3 months and 68.3% at final palpation (>3 months). Mean tumour size by clinical palpation at T=0 was 39.1mm (95% CI 34.8-43.4mm), and decreased to 23.0mm (95% CI 18.7-27.2mm) and 16.7 mm (95% CI 12.6-20.8) at T=3 and T>3 months, respectively (p=0.001). Final radiological response rates at the end of treatment for MRI (n=37), ultrasound (n=77) and mammography (n=56) were 70.3%, 41.6% and 48.2%, respectively. Feasibility of BCS improved from 61.8% to 70.6% (McNemar p=0.012). CONCLUSION: 6 months of neoadjuvant exemestane therapy helps reduce mean tumour size further in strongly ER-positive BC patients without significant side-effects compared to 3 months. Nevertheless, some patients still experience disease progression under exemestane. Feasibility of breast conservation rates improved by almost 10%.

Can Zoledronic Acid be Beneficial for Promoting Tumor Response in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy?

The antitumor effect of bisphosphonates (BPs) is under increasing scrutiny. Preclinical and clinical evidence has shown that BPs might sensitize breast tumors to chemotherapy. Here, we present a review of current preclinical and clinical evidence for antitumor effects of BPs, and evaluate how BPs might play a role in neoadjuvant treatment of women with breast cancer.

Timing of the sentinel lymph node biopsy in breast cancer patients receiving neoadjuvant therapy - recommendations for clinical guidance.

Neoadjuvant chemotherapy (NAC) is an increasingly important component in the treatment of both locally advanced and early-stage breast cancer. With this, a debate on the timing of the sentinel lymph node biopsy (SLNB) has emerged. At the end of the last century, the SLNB was introduced as an axillary staging modality, and this paper aims to further elucidate this issue in the context of NAC. We compiled available data on the SLNB after NAC and provide clinical guidance for timing the SLNB in this context. On the basis of our findings, we recommend that the SLNB can be performed after NAC in all cases. In patients with a clinically node-negative (cN0) status prior to NAC, the SLNB should be performed after NAC, and in case of a histologically confirmed negative SLNB, a completion axillary lymph node dissection (ALND) has no added value and can be omitted. In patients with clinically positive nodal involvement (cN+) prior to NAC, all axillary surgery can also be performed after NAC.

Specific adverse events predict survival benefit in patients treated with tamoxifen or aromatase inhibitors: an international tamoxifen exemestane adjuvant multinational trial analysis.

PURPOSE: Specific adverse events (AEs) associated with endocrine therapy and related to depletion or blocking of circulating estrogens may be related to treatment efficacy. We investigated the relationship between survival outcomes and specific AEs including vasomotor symptoms (VMSs), musculoskeletal adverse events (MSAEs), and vulvovaginal symptoms (VVSs) in postmenopausal patients with breast cancer participating in the international Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. PATIENTS AND METHODS: Primary efficacy end points were disease-free survival (DFS), overall survival (OS), and distant metastases (DM). VMSs, MSAEs, and VVSs arising in the first year of endocrine treatment were considered. Patients who did not start or who discontinued their allocated therapy and/or had an event (recurrence/death) within 1 year after randomization were excluded. Landmark analyses and time-dependent multivariate Cox proportional hazards models assessed survival differences up to 5 years from the start of treatment. RESULTS: A total of 9,325 patients were included. Patients with specific AEs (v nonspecific or no AEs) had better DFS and OS (multivariate hazard ratio [HR] for DFS: VMSs, 0.731 [95% CI, 0.618 to 0.866]; MSAEs, 0.826 [95% CI, 0.694 to 0.982]; VVSs, 0.769 [95% CI, 0.585 to 1.01]; multivariate HR for OS: VMSs, 0.583 [95% CI, 0.424 to 0.803]; MSAEs, 0.811 [95% CI, 0.654 to 1.005]; VVSs, 0.570 [95% CI, 0.391 to 0.831]) and fewer DM (VMSs, 0.813 [95% CI, 0.664 to 0.996]; MSAEs, 0.749 [95% CI, 0.601 to 0.934]; VVSs, 0.687 [95% CI, 0.436 to 1.085]) than patients not reporting these symptoms. Increasing numbers of specific AEs were also associated with better survival outcomes. Outcomes were unrelated to treatment allocation. CONCLUSION: Certain specific AEs are associated with superior survival outcomes and may therefore be useful in predicting treatment responses in patients with breast cancer treated with endocrine therapy.

Influence of semi-quantitative oestrogen receptor expression on adjuvant endocrine therapy efficacy in ductal and lobular breast cancer - a TEAM study analysis.

BACKGROUND: Multiple studies suggest better efficacy of chemotherapy in invasive ductal breast carcinomas (IDC) than invasive lobular breast carcinomas (ILC). However, data on efficacy of adjuvant endocrine therapy regimens and histological subtypes are sparse. This study assessed endocrine therapy efficacy in IDC and ILC. The influence of semi-quantitative oestrogen receptor (ER) expression by Allred score was also investigated. METHODS: Dutch and Belgian patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial were randomized to exemestane (25mg daily) alone or following tamoxifen (20mg daily) for 5 years. Inclusion was restricted to IDC and ILC patients. Histological subtype was assessed locally; ER expression was centrally reviewed according to Allred score (ER-poor (<7; n=235); ER-rich (7; n=1789)). Primary end-point was relapse-free survival (RFS), which was the time from randomization to disease relapse. FINDINGS: Overall, 2140 (82%) IDC and 463 (18%) ILC patients were included. RFS was similar for both endocrine treatment regimens in IDC (hazard ratio (HR) for exemestane was 0.83 (95%confidence interval (CI) 0.67-1.03)), and ILC (HR 0.69 (95%CI 0.45-1.06)). Irrespective of histological subtype, patients with ER-rich Allred scores allocated to exemestane alone had an improved RFS (multivariable HR 0.71 (95%CI 0.56-0.89)). In contrast, patients with ER-poor Allred scores allocated to exemestane had a worse RFS (multivariable HR 2.33 (95%CI 1.32-4.11)). Significant effect modification by ER-Allred score was confirmed (multivariable p=0.003). INTERPRETATION: Efficacy of endocrine therapy regimens was similar for IDC and ILC. However, ER-rich patients showed superior efficacy to upfront exemestane, while ER-poor patients had better outcomes with sequential therapy, irrespective of histological subtype, emphasising the relevance of quantification of ER expression.

Two decades of percutaneous transjejunal biliary intervention for benign biliary disease: a review of the intervention nature and complications.

OBJECTIVE: To assess outcomes of percutaneous transjejunal biliary intervention (PTJBI) in terms of success and effectiveness in patients with a Roux-en-Y hepaticojejunostomy for benign biliary strictures and stones. METHODS: Clinical and radiographic records of 63 patients with a Roux-en-Y choledochojejunostomy or hepaticojejunostomy for benign disease who underwent at least one PTJBI between 1986 and 2007 were reviewed. Effectiveness was determined by successful access rate, rates of stricture dilatation and/or stone extraction, morbidity, complications and hospitalisation. RESULTS: PTJBI was attempted 494 times. Successful access to the Roux-en-Y was accomplished in 93% of interventions. After access to the Roux-en-Y was granted, all strictures were effectively dilated. Ninety-seven percent of extraction attempts of intrahepatic calculi were successful. The median number of interventions per patient was five. The median interval between interventions was 51.5 weeks (range 2.7-1,279.6 weeks). The early complication rate was 3%. Morbidity, measured in terms of cholangitis episodes was 14%, in 25 out of 63 patients. Mean hospitalisation was 4.1 nights per year. CONCLUSION: PTJBI is safe and effective in treating benign biliary strictures and/or calculi. High success rates and short hospitalisation periods, together with few complications make it a well-accepted and integral part of managing complex biliary problems.