Heparin-induced thrombocytopenia in lower extremity free tissue transfers.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) an immunologically mediated reaction to heparin products, can lead to severe thrombocytopenia and potentially life-threatening thrombotic events. In microsurgery, a missed or delayed diagnosis of HIT can cause complications requiring revision operations, flap loss, or limb loss. Surgeons must remain vigilant for this uncommon yet potentially devastating condition and keep abreast of management strategies. METHODS: CPT and ICD-10 codes in electronic medical records were used to collect demographic information, clinical courses, and outcomes for patients with a HIT diagnosis who underwent lower extremity free tissue transfer in one institution. RESULTS: The authors' institution performed 415 lower extremity free flaps in 411 patients during the 10-year study period. Flap salvage rate was 71% for compromised lower extremity flaps without HIT, and 25% in those with HIT. Four patients (four flaps) met study inclusion criteria during the study period. Three of the four flaps failed and were later debrided; one was rescued after a takeback for anastomosis revision. Two patients successfully underwent a delayed second free flap procedure after recovery, and one was salvaged with a pedicled muscle flap. CONCLUSIONS: Surgeons should monitor for HIT by establishing coagulation panel and platelet count baselines and trending these values in the early post-operative period for patients treated with heparin products. The 4T score can be used to screen for HIT with high clinical suspicion. Arterial thrombosis or poor flap perfusion despite sound microvascular technique could suggest HIT. Surgical and medical management including strict heparin avoidance can prevent adverse events for these patients.

Safety and efficacy of immediate autologous breast reconstruction after mastectomy in patients undergoing neoadjuvant chemoradiotherapy for locally advanced breast cancer.

PURPOSE: Immediate autologous breast reconstruction (IABR) offers fewer surgeries with better psychosocial, quality of life and aesthetic outcomes. In high-risk patients or those with locally advanced breast cancer (LABC), adjuvant postmastectomy radiotherapy decreases local recurrence and improves survival. However, it has negative effects on the reconstructed flap. Reversing the treatment protocol using neoadjuvant radiotherapy may minimise the negative effects on the reconstructed breast in women requesting IABR. We assessed the safety and efficacy of women who underwent mastectomy and IABR post-neoadjuvant chemoradiotherapy (NACRT) for LABC. METHODOLOGY: A cohort study using a retrospective and prospective analysis was performed on women with LABC who underwent mastectomy and IABR post-NACRT between 1998 and 2018. All reconstructions were performed by oncoplastic breast surgeons from a single unit. Outcome measures analysed included surgical complications, flap failure, loco-regional recurrence, overall and disease-free survival. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the institutional review board. RESULTS: A total of 28 women with a median age of 50 (33-64) were included. 25% underwent TRAM flap and 75% underwent LD flap reconstruction. The median period of follow-up was 61 months. Post-NACRT, 35.7% achieved complete pathological response (PCR). 3/28 (10.7%) had early complications (2 implant and 1 donor site infection). 7% underwent revision surgery. There was no flap loss. 1/28 (3.5%) had loco-regional recurrence, 3.2% had distant metastasis, and 2.5% had breast cancer related mortality. CONCLUSION: In women with LABC, NACRT followed by mastectomy and IABR is safe and may not compromise oncological and cosmetic outcomes. If offers the benefits of immediate breast reconstruction and avoids delaying adjuvant therapy.

CXCR4-CCR7 Heterodimerization Is a Driver of Breast Cancer Progression.

Metastatic breast cancer has one of the highest mortality rates among women in western society. Chemokine receptors CXCR4 and CCR7 have been shown to be linked to the metastatic spread of breast cancer, however, their precise function and underlying molecular pathways leading to the acquisition of the pro-metastatic properties remain poorly understood. We demonstrate here that the CXCR4 and CCR7 receptor ligands, CXCL12 and CCL19, cooperatively bind and selectively elicit synergistic signalling responses in invasive breast cancer cell lines as well as primary mammary human tumour cells. Furthermore, for the first time, we have documented the presence of CXCR4-CCR7 heterodimers in advanced primary mammary mouse and human tumours where number of CXCR4-CCR7 complexes directly correlate with the severity of the disease. The functional significance of the CXCR4-CCR7 association was also demonstrated when their forced heterodimerization led to the acquisition of invasive phenotype in non-metastatic breast cancer cells. Taken together, our data establish the CXCR4-CCR7 receptor complex as a new functional unit, which is responsible for the acquisition of breast cancer cell metastatic phenotype and which may serve as a novel biomarker for invasive mammary tumours.

Long-term outcomes of breast reconstruction and the need for revision surgery.

BACKGROUND: Breast reconstruction (BR) often forms part of a patient's breast cancer journey. Revision surgery may be required to maintain the integrity of a BR, although this is not commonly reported in the literature. Different reconstructive methods may have differing requirements for revision. It is important for patients and surgeons to understand the factors leading to the need for revision surgery. METHODS: This retrospective cohort study analyses BRs performed by oncoplastic breast surgeons in public and private settings between 2005 and 2014, with follow-up until December 2018. Surgical and patient factors were examined, including types of BR, complications and reasons for revision surgery. RESULTS: A total of 390 women with 540 reconstructions were included, with a median follow-up of 61 months. Twenty-eight percent (151/540) of reconstructions required at least one revision operation. Overall, implant-based reconstructions (direct-to-implant [DTI] and two-stage expander-implant) had a higher revision rate compared to pedicled flap reconstructions (odds ratio 1.91, 95% confidence interval 1.08, 3.38). DTI reconstructions had the highest odds, and pedicled flap without implants the lowest odds of requiring revision. Post-reconstruction radiotherapy increased the chance of revision surgery, while pre-reconstruction radiotherapy did not. Odds of revision were higher in implant-based reconstructions compared to pedicled flap reconstructions that had radiotherapy. Other factors increasing the rates of revision surgery were being a current smoker and post-operative infection. CONCLUSION: Almost one-third of reconstructive patients require revision surgery. Autologous pedicled flap reconstructions have lower rates of revision compared to implant-based reconstructions. Radiotherapy increases the need for revision surgery, particularly in implant-based reconstructions.

Publisher Correction: ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism.

It is well accepted that cancers co-opt the microenvironment for their growth. However, the molecular mechanisms that underlie cancer-microenvironment interactions are still poorly defined. Here, we show that Rho-associated kinase (ROCK) in the mammary tumour epithelium selectively actuates protein-kinase-R-like endoplasmic reticulum kinase (PERK), causing the recruitment and persistent education of tumour-promoting cancer-associated fibroblasts (CAFs), which are part of the cancer microenvironment. An analysis of tumours from patients and mice reveals that cysteine-rich with EGF-like domains 2 (CRELD2) is the paracrine factor that underlies PERK-mediated CAF education downstream of ROCK. We find that CRELD2 is regulated by PERK-regulated ATF4, and depleting CRELD2 suppressed tumour progression, demonstrating that the paracrine ROCK-PERK-ATF4-CRELD2 axis promotes the progression of breast cancer, with implications for cancer therapy.

Extended duration of adjuvant aromatase inhibitor in breast cancer: a meta-analysis of randomized controlled trials.

BACKGROUND: The risk of hormone positive breast cancer extends beyond 5 years. Extended duration of tamoxifen to 10 years has been shown to improve overall survival (OS) and disease-free survival (DFS). In post-menopausal women aromatase inhibitor (AI) is the gold standard for adjuvant endocrine therapy. Several randomized controlled trials (RCTs) showed benefit with extending the duration of AIs in post-menopausal women. However, the duration and the overall benefit is still controversial. METHODS: Eligible 8 RCTs comprising of 17,190 participants were included in this meta-analysis. RESULTS: Extending the duration of AI did not show any statistically significant advantage in OS with OR of 1.033 (95% CI: 0.925-1.154, P=0.56), DFS OR of 1.049 (95% CI: 0.930-1.185, P=0.435), recurrence-free survival (RFS) OR of 1.063 (95% CI: 0.952-1.187, P=0.276), and contralateral breast cancer (CBC) OR of 1.094 (95% CI: 0.920-1.301, P=0.311). Higher rates of side-effects of arthralgia, myalgia, hot flushes and bone toxicity was seen among the extended AI group. CONCLUSIONS: Based on this meta-analysis and current literature review, extended use of AI after 5 years of endocrine therapy should be used in selected women with high risk tumour factors. Molecular markers and genomic profiling may assist in identifying the high-risk patients. It is important to consider quality of life and patient satisfaction when considering extending the duration of AI.

Importance of Interaction between Integrin and Actin Cytoskeleton in Suspension Adaptation of CHO cells.

The biopharmaceutical production process relies upon mammalian cell technology where single cells proliferate in suspension in a chemically defined synthetic environment. This environment lacks exogenous growth factors, usually contributing to proliferation of fibroblastic cell types such as Chinese hamster ovary (CHO) cells. Use of CHO cells for production hence requires a lengthy 'adaptation' process to select clones capable of proliferation as single cells in suspension. The underlying molecular changes permitting proliferation in suspension are not known. Comparison of the non-suspension-adapted clone CHO-AD and a suspension-adapted propriety cell line CHO-SA by flow cytometric analysis revealed a highly variable bi-modal expression pattern for cell-to-cell contact proteins in contrast to the expression pattern seen for integrins. Those have a uni-modal expression on suspension and adherent cells. Integrins showed a conformation distinguished by regularly distributed clusters forming a sphere on the cell membrane of suspension-adapted cells. Actin cytoskeleton analysis revealed reorganisation from the typical fibrillar morphology found in adherent cells to an enforced spherical subcortical actin sheath in suspension cells. The uni-modal expression and specific clustering of integrins could be confirmed for CHO-S, another suspension cell line. Cytochalasin D treatment resulted in breakdown of the actin sheath and the sphere-like integrin conformation demonstrating the link between integrins and actin in suspension-adapted CHO cells. The data demonstrates the importance of signalling changes, leading to an integrin rearrangement on the cell surface, and the necessity of the reinforcement of the actin cytoskeleton for proliferation in suspension conditions.

Review of the role of sentinel node biopsy in cutaneous head and neck melanoma.

Sentinel node biopsy (SNB) is recommended for selected melanoma patients in many parts of the world. This review examines the evidence surrounding the accuracy and prognostic value of SNB and completion neck dissection in head and neck melanoma. Sentinel nodes were identified in an average of 94.7% of head and neck cases compared with 95.3-100% in all melanoma cases. More false-negative sentinel nodes were found in head and neck cases. A positive sentinel node was associated with both lower disease-free survival (53.4 versus 83.2%) and overall survival (40 versus 84%). We conclude that SNB should be offered to all patients with intermediate and high-risk melanomas in the head and neck area. To date, evidence does not exist to demonstrate the safety of avoiding completion lymph node dissection in sentinel node-positive patients with head and neck melanoma.

The effect of smoking and major vein resection on post-therapy lymphedema in soft tissue sarcomas treated with neoadjuvant radiation and limb-salvage surgery.

BACKGROUND: Neoadjuvant therapy with radiation +/- chemotherapy is an accepted management for soft tissue sarcomas (STS). The incidence of post-therapy lymphedema is around 30%. The purpose of this study was to identify variables that predict for post-therapy lymphedema. METHODS: From 2000 to 2010, 132 patients with STS were treated with neoadjuvant radiation +/- chemotherapy followed by resection. Patient variables and treatment outcomes were reviewed. Presence of lymphedema was determined by the treating physician. The Fisher exact test was used for univariate analysis and logistic regression was used for multivariate analysis. RESULTS: Median follow-up was 3.1 years. Of the lower extremity STS, major veins were sacrificed in 34% of patients. Lymphedema occurred in 22.4% of patients. Smoking negatively predicted for lymphedema on univariate analysis (P=0.007), and sacrifice of a major vein was associated with an increased risk of lymphedema (P=0.02). On multivariate analysis, smoking (P=0.02, odds ratio 0.31) negatively predicted for and sacrifice of a major vein (P=0.03, odds ratio 2.7) positively predicted for lymphedema. CONCLUSIONS: There may be an association between smoking and decrease post-therapy lymphedema. Also, patients who undergo resection of a major vein seem to be more prone to post-therapy lymphedema.

Palpation as a useful diagnostic tool for skin lesions.

INTRODUCTION: Early identification and accurate diagnosis of malignant pigmented skin lesions is essential for effective management and cost containment. The aim was to investigate the additional value of tactile descriptive information from lesion palpation on the diagnostic accuracy of pigmented skin lesions by medical students using computer-driven learning. METHODS: Sixth year medical students (n = 152) from the University of Adelaide were invited to participate in an online teaching module on pigmented skin lesions. Users were asked to describe, diagnose and manage 15 pigmented skin lesions in three separate case studies based on pertinent clinical history and visual images of the lesions. Tactile descriptive information was then provided and users were asked to reflect on their diagnosis and management. RESULTS: A total of 66 (43%) of the sixth year students successfully completed the online module. Diagnostic accuracy improved significantly with the provision of tactile descriptive information for seborrhoeic keratosis (p = 0.012), basal cell carcinoma (p = 0.001), squamous cell carcinoma (p = 0.02), and dysplastic naevi (p = 0.035). Tactile descriptive information was stated by 23% of medical students to be important in the clinical diagnosis of pigmented skin lesion. Students managed all malignant pigmented skin lesions with either appropriate biopsy or specialist referral. CONCLUSIONS: Palpation information about skin lesions offers useful information for improvement of diagnostic accuracy in an online computer learning setting for medical students.

Nutlin-3a efficacy in sarcoma predicted by transcriptomic and epigenetic profiling.

Nutlin-3a is a small-molecule antagonist of p53/MDM2 that is being explored as a treatment for sarcoma. In this study, we examined the molecular mechanisms underlying the sensitivity of sarcomas to Nutlin-3a. In an ex vivo tissue explant system, we found that TP53 pathway alterations (TP53 status, MDM2/MDM4 genomic amplification/mRNA overexpression, MDM2 SNP309, and TP53 SNP72) did not confer apoptotic or cytostatic responses in sarcoma tissue biopsies (n = 24). Unexpectedly, MDM2 status did not predict Nutlin-3a sensitivity. RNA sequencing revealed that the global transcriptomic profiles of these sarcomas provided a more robust prediction of apoptotic responses to Nutlin-3a. Expression profiling revealed a subset of TP53 target genes that were transactivated specifically in sarcomas that were highly sensitive to Nutlin-3a. Of these target genes, the GADD45A promoter region was shown to be hypermethylated in 82% of wild-type TP53 sarcomas that did not respond to Nutlin-3a, thereby providing mechanistic insight into the innate ability of sarcomas to resist apoptotic death following Nutlin-3a treatment. Collectively, our findings argue that the existing benchmark biomarker for MDM2 antagonist efficacy (MDM2 amplification) should not be used to predict outcome but rather global gene expression profiles and epigenetic status of sarcomas dictate their sensitivity to p53/MDM2 antagonists.

Multimodality management of metastatic patients with soft tissue sarcomas may prolong survival.

OBJECTIVES: Patients who develop metastatic disease from soft tissue sarcoma have a poor prognosis. The purpose of this study was to identify metastatic survival rates and identify prognostic variables that predict for these outcomes. METHODS: Between 2000 and 2010, 182 patients with stage I to IV primary soft tissue sarcomas of the extremity and trunk were treated with multimodality treatment. Fifty-five patients developed or presented with metastasis. We retrospectively analyzed prognostic factors for metastatic survival. Metastatic survival between groups was compared with the log-rank test. Survival curves were estimated by Kaplan-Meier plots. Multivariate analysis was performed using the Cox proportional hazards model. RESULTS: Median follow-up was 3.1 years. Median metastatic survival was 24.2 months. Median metastatic survival in those undergoing multimodality therapies was 40 versus 22 months in those receiving single modality treatments. In single predictor Cox models, age, stage, number of lung metastases, location of metastases, and primary disease were significant for metastatic survival. On multivariate analysis, number of pulmonary metastases, histology, stage, and location of primary disease predicted for metastatic survival. Patients who had pulmonary-only disease had improved metastatic survival versus those that had extrapulmonary with or without pulmonary metastatic disease (38 vs. 15 mo). Patients who had ≤5 pulmonary metastasis had improved metastatic survival versus those that had >5 pulmonary lesions (55 vs. 22 mo). CONCLUSIONS: This analysis shows that >5 pulmonary metastasis, malignant fibrous histiocytoma histology, stage III disease, and proximal lower extremity sarcomas are associated with decreased metastatic survival. Moreover, aggressive multimodality management of metastatic disease may prolong metastatic survival.

Prognostic variables in patients with primary soft tissue sarcoma of the extremity and trunk treated with neoadjuvant radiotherapy or neoadjuvant sequential chemoradiotherapy.

BACKGROUND: Neoadjuvant radiotherapy (NRT) is an effective strategy to treat soft tissue sarcomas (STS). However, the role of neoadjuvant chemoradiotherapy (NCRT) remains to be determined. METHODS: From May 1999 to July 2010, 112 patients with localized STS of the extremity and trunk who were treated with NRT or NCRT followed by surgery were retrospectively reviewed. Clinical outcomes including overall survival (OS), disease-free survival (DFS), and distant metastasis free survival (DMFS) were calculated using Kaplan-Meier survival analyses. Prognostic variables were determined by univariate (UVA) and multivariate analyses (MVA). RESULTS: Median follow-up was 37 months. Median RT dose was 50 Gy. Forty-nine patients received NCRT. Overall limb-preservation rate was 99% and local control was 97%. The estimated 3-year OS, DFS, and DMFS were 86%, 68%, and 72%, respectively. Age was the only variable to predict for OS, DFS and DMFS on UVA. Age ≥ 70 predicted for poor OS, stage III disease predicted for poor DFS and DMFS, and the addition of chemotherapy predicted for improved DMFS on MVA. CONCLUSIONS: Excellent rates of local control and limb-preservation were observed in patients with primary STS treated with neoadjuvant therapy followed by surgery. Neoadjuvant sequential chemotherapy followed by radiotherapy may be considered for young patients with stage III STS.

Management of ductal carcinoma in situ according to Van Nuys Prognostic Index in Australia and New Zealand.

INTRODUCTION: Clinicians often use the Van Nuys Prognostic Index (VNPI) to determine management of ductal carcinoma in situ (DCIS). The VNPI uses age, extent of DCIS, pathological grade and resection margins to stratify patients into three groups pertaining to risk of local recurrence: low-risk (where breast-conserving surgery - BCS - alone appears adequate), intermediate-risk (where BCS plus radiotherapy is recommended) and high-risk (where mastectomy may be the safest option). The purpose of this study was to determine patterns of management of DCIS in Australia and New Zealand according to the VNPI. METHODS: Using the National Breast Cancer Audit for the period 2004-2009, 4578 cases of DCIS were identified where complete data were available. Patterns of management according to the VNPI were determined. The chi-squared test was used for statistical analysis. RESULTS: In VNPI group 1, 77% of patients were treated with BCS compared with 63% in group 2 and 32% in group 3. Of patients in group 1 who underwent BCS, 58% also received adjuvant radiotherapy, compared with 80% in group 2. In group 3, 68% were treated with mastectomy, and of those who underwent BCS, 86% received radiotherapy. Overall, 23% of DCIS cases did not conform to best practice according to individual VNPI prognostic groupings. CONCLUSIONS: Significant differences in the management of DCIS according to VNPI groups were observed. The results suggest the possibility that some patients in the low-risk group were over-treated, while a proportion of patients in the intermediate- and high-risk groups were under-treated.

Use of trastuzumab in Australia and New Zealand: results from the National Breast Cancer Audit.

BACKGROUND: Trastuzumab increases disease-free and overall survival in HER-2-positive, early breast cancer. In 2007, the National Breast and Ovarian Cancer Centre recommended that patients with HER-2 positive cancers (node positive or node negative tumours >1 cm) be offered adjuvant trastuzumab with chemotherapy. The aim of this study was to evaluate recent trends in trastuzumab therapy in Australia and New Zealand. METHODS: Following data were obtained from the National Breast Cancer Audit for patients treated between 2006 and 2008: tumour size, number of cases recorded per surgeon per year, location of hospital, HER-2 receptor status, age, lymph node status, chemotherapy and trastuzumab treatment. RESULTS: Data were available from 23,290 patients. During the study period, the percentage of breast cancers tested for HER-2 rose from 77% to 91%. Patients over 70 had fewer HER-2 tests than their younger counterparts. Fourteen percent of tumours were HER-2 positive; the proportion treated with trastuzumab in 2006, 2007 and 2008 was 50%, 66% and 74%, respectively. Significantly more node-positive patients (77%) were given trastuzumab than node-negative patients (52%). All the patients prescribed trastuzumab also received chemotherapy. Patients under 70 years, patients treated in Australia and patients treated by higher caseload surgeons were more likely to be prescribed trastuzumab than those over 70, patients in New Zealand and patients treated by lower caseload surgeons. CONCLUSIONS: Trastuzumab-prescribing trends conform to the published guidelines. However, older patients and those with HER-2 positive, node-negative tumours >1 cm may be undertreated in some cases.

Coverage of Megaprosthesis with Human Acellular Dermal Matrix after Ewing's Sarcoma Resection: A Case Report.

A 23-year-old female with Ewing's Sarcoma underwent tibial resection and skeletal reconstruction using proximal tibial allograft prosthetic reconstruction with distal femur endoprosthetic reconstruction and rotating hinge. Human acellular dermal matrix, (Alloderm, LifeCell, Branchburg, NJ, USA), was used to wrap the skeletal reconstruction. Soft tissue reconstruction was completed with a rotational gastrocnemius muscle flap and skin graft. Despite prolonged immobilization, the patient quickly regained full range of motion of her skeletal reconstruction. Synthetic mesh, tapes and tubes are used to perform capsule reconstruction of megaprosthesis. This paper describes the role of human acellular dermal matrix in capsule reconstruction around a megaprosthesis.

Ultrasound-assisted lipoplasty in addition to suction-assisted lipoplasty for perforator free flap thinning.

Perforator flaps are routinely used in upper- and lower-extremity reconstruction. Increased usage of these flaps as well as their intraoperative thinning has been described; however, there are limited reports of thinning in the postoperative period. From 2005 to 2010, thinning procedures were performed on 11 patients with 11 flaps. There were six males and five females in this series. Three flaps were deep inferior epigastric artery flaps, six flaps were anterolateral thigh flaps, and two were medial thigh flaps. After the initial microvascular reconstructive procedure, the patient underwent a second procedure where ultrasound-assisted lipoplasty, suction-assisted lipoplasty, flap advancement, and excision were performed. With aggressive, staged thinning procedures, there were no cases of partial or complete flap necrosis. Given the increasing number of perforator flaps being performed for upper- and lower-extremity reconstruction, a larger number of cutaneous flaps will need postoperative thinning. Ultrasound-assisted lipoplasty has been found to be a useful modality in revision of these flaps.

Adjuvant high dose rate brachytherapy for soft tissue sarcomas: initial experience report.

PURPOSE: Adjuvant high-dose-rate brachytherapy (HDRBT) offers advantages over low dose rate brachytherapy (LDRBT), although there are little data on local tumor control and treatment related toxicity. We report outcome in patients with primary, recurrent, and metastatic extremity and superficial trunk soft tissue sarcoma. MATERIAL AND METHODS: Eleven patients (12 sites) with intermediate or high grade sarcoma were treated with adjuvant HDRBT following surgical resection. Patients were treated at 3.4 Gy fractions delivered twice daily to a total dose of 34 Gy (1 patient received 9 fractions). RESULTS: With median follow-up of 20.8 months, 1 patient developed a local recurrence. 2-year local control and overall survival are 89% and 71%, respectively. Wound complications occurred in 3 sites. Two of the wound complications developed in the area of previous external beam radiotherapy (EBRT). CONCLUSION: Surgical resection followed by HDRBT is associated with excellent early local tumor control and acceptable wound complication.