Angiosarcoma: a 10-year retrospective study from a high-volume UK regional referral centre.

PURPOSE: Angiosarcoma (AS) is a rare malignancy with considerable heterogeneity seen in its aetiology, anatomical location, and clinicopathological behaviour. Diagnosis is often delayed and prognosis poor. The purpose of this study was to perform a retrospective review of all cases of AS over 10 years at a high-volume regional UK referral centre. METHODS/PATIENTS: We reviewed all cases of AS discussed at the sarcoma multidisciplinary meetings of University Hospitals Birmingham NHS Foundation Trust from September 2013 to August 2023. Demographic and clinicopathologic features at diagnosis, approaches to treatment, and outcomes were compared between four AS subtypes. RESULTS: A total of 130 cases were identified. The median age at diagnosis was 71 years, with the majority being female (78%). The most common AS subtype was radiation-induced AS (RIAS) (n = 72; 55%), followed by primary cutaneous (n = 28; 22%), primary non-cutaneous (n = 25; 19%), and AS secondary to lymphoedema (n = 5; 4%). Metastases were present at diagnosis in 18% of patients. Treatment was with surgery in the majority of patients (71%). The median survival for the cohort was 30 months (95% CI 20-40), although this differed significantly by AS subtype (p < 0.001), ranging from 5 months in primary non-cutaneous AS to 76 months in RIAS. CONCLUSION: RIAS is the most common AS subtype, with surgery the only potentially curative treatment modality. Overall prognosis varies significantly by subtype. An international consensus on classification of AS subtypes is required to allow meaningful comparisons across studies and/or a prospective multi-centre registry.

Enhanced Recovery Pathways for Flap-Based Reconstruction: Systematic Review and Meta-Analysis.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) pathways are known to improve patient outcomes after surgery. In recent years, there have been growing interest in ERAS for reconstructive surgery. OBJECTIVES: To systematically review and summarise literature on the key components and outcomes of ERAS pathways for autologous flap-based reconstruction. DATA SOURCES: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Current Controlled Trials, World Health Organization International Clinical Trials Registry Platform and reference lists of relevant studies. INCLUSION CRITERIA: All primary studies of ERAS pathways for free and pedicled flap-based reconstructions reported in the English language. OUTCOME MEASURES: The primary outcome measure was length of stay. Secondary outcomes were complication rates including total flap loss, partial flap loss, unplanned reoperation within 30 days, readmission to hospital within 30 days, surgical site infections and medical complications. RESULTS: Sixteen studies were included. Eleven studies describe ERAS pathways for autologous breast reconstructions and five for autologous head and neck reconstructions. Length of stay was lower in ERAS groups compared to control groups (mean reduction, 1.57 days; 95% CI, - 2.15 to - 0.99). Total flap loss, partial flap loss, unplanned reoperations, readmissions, surgical site infections and medical complication rates were similar between both groups. Compliance rates were poorly reported. CONCLUSION: ERAS pathways for flap-based reconstruction reduce length of stay without increasing complication rates. ERAS pathways should be adapted to each institution according to their needs, resources and caseload. There is potential for the development of ERAS pathways for chest wall, perineum and lower limb reconstruction. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

The Ever-Present Costs of Cosmetic Surgery Tourism: A 5-Year Observational Study.

BACKGROUND: Cosmetic surgery tourism is an ever-growing industry. Despite its associated risks, an increasing number of patients are presenting to NHS services with resulting complications. This study aims to evaluate the current presentation patterns for complications in cosmetic surgery tourism, and the financial burden to the NHS reported by a single UK level one trauma centre in Birmingham, UK. METHODS: From 2015 to 2020, all patients presenting to the department of plastic surgery with complications of cosmetic surgery performed outside of the UK were included. Data were collected for patients' characteristics including demographics, performed procedures, complications and treatment. A cost analysis was performed for each patient using published "National Schedule of NHS Costs." RESULTS: A total of 26 patients presented to our hospital within the study period. All patients were female, with the mean age being 35.1 years (range 22-55years). A total of 32 cosmetic procedures were undertaken, with the majority performed in Turkey (n = 14). Abdominoplasty was the most common procedure, followed by gluteal enhancement surgery. The total financial cost to the NHS from all cosmetic surgery-related complications was £152,946, with an average cost per patient of £5,882.54 (range £362-£26,585). CONCLUSION: Patients seek out medical tourism for multiple reasons including cost savings, shorter waiting times and surgical expertise. The costs displayed should predominantly be viewed as a reflection of the detrimental effect these complications can have on patients' lives. Global governing bodies should focus efforts on educating patients and raising awareness on this ever-prevalent issue. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Avoiding the night terrors: the effect of circadian rhythm on post-operative urine output and blood pressure in free flap patients.

Multiple studies demonstrate the importance of goal-directed fluid regimens in avoiding complications. These regimens do not take account of circadian fluctuations in urine output (UO), MAP (mean arterial pressure) and pulse rate (PR). This is the first study that aims to demonstrate the effect of circadian rhythm on these haemodynamic parameters in post-operative patients with free flaps, as well as analysing clinicians' response to these variations. Retrospective analysis of 116 patients with free flaps. Records were assessed for UO, MAP, IV fluid infusion rate, oral fluid intake. Parameters were measured from 8 am to 8 pm (diurnal) and from 8 pm to 8 am (nocturnal) in the first 48 h post operatively. Patients with diabetes or hypertension were excluded. Mean diurnal UO rate (1.7 ml/kg/hr) was higher than nocturnal UO rate (0.7 ml/kg/hr); and mean diurnal MAP (93) was higher than nocturnal MAP (73.8). Mean diurnal IV infusion rate was 1.25 ml/kg/hr (lower) and mean nocturnal infusion rate 1.81 ml/kg/hr (higher). These differences were all statistically significant by paired student t-test (p < 0.05). This study demonstrates that circadian rhythm has a statistically significant impact on UO, MAP and PR. UO, MAP and PR are expected to dip overnight. This dip is normal and does not necessarily need to be treated by increasing IV fluids to avoid over filling of free flap patients.

Orthoplastic Management of Open Midfoot Injuries: Is Functional Limb Salvage Possible?

High energy open midfoot injuries are uncommon but devastating injuries. A combination of complex fracture dislocations and soft tissue injury patterns render reconstruction challenging. The aim of this study was to assess the surgical and patient reported outcomes following orthoplastic management of open midfoot injuries in a Major Trauma Center. A retrospective review of all open midfoot fractures admitted to our unit between January 2015 and December 2016 was undertaken. Demographics, operative details, complications, additional surgeries, and patient reported outcomes in the form of EQ-5D and Enneking scores were collected. Fifteen patients were identified (13 male, mean age 39.2 years). One patient underwent amputation at initial debridement and 8 required additional debridement. Of these 8 patients, 3 had an amputation during their index admission. In the limb salvage group (11 patients), definitive soft tissue cover involved free flaps in 6 patients, split skin graft in 3 patients, and delayed primary closure in 2 patients. Definitive orthopedic treatment was internal fixation in 8 and external fixation in 3 patients. Two patients required a Masquelet procedure for bone loss. One patient had a toe amputation and 1 had a below knee amputation for deep infection. The median EQ-5D score was 66 (interquartile range 43), and the median Enneking score was 20.5 (interquartile range 9). Limb salvage following open midfoot fractures is technically possible in most cases, however this often involves multiple procedures and the outcomes are variable and difficult to predict. Patients should be carefully counseled, and amputation considered in all such cases.

Comment on: "A structured pathway for accelerated postoperative recovery reduces hospital stay and cost of care following microvascular breast reconstruction without increased complications".

We read with great interest a recent article by O'Neill et al. on the implementation of an accelerated postoperative recovery protocol following DIEP flap breast reconstruction. Our department has formally introduced a DIEP Enhanced Recovery After Surgery (ERAS) Pathway in May 2019. Although in a much smaller sample size, our results were similar to this article and we would agree with the authors' conclusion that implementation of such protocol could effectively reduce the length of inpatient stay (LoS) and cost of care, without compromising patient care nor increasing complication rates. Prior to the introduction of ERAS Pathway, 28 of our patients who had DIEP between November 2018 and May 2019 had an mean LoS of 7.1 days (median 6 days, range 5-21 days); whereas 27 patients who experienced the ERAS Pathway between May and December 2019 had an mean LoS of 4.8 days (median 5 days, range 3-7 days). The cost of inpatient stay in a normal ward at our hospital is approximately £232 per patient per day. By reducing an extra 2.3 days of inpatient stay, our Trust could save at least an average of £32,016 per annum with the estimated 60 DIEP performed annually at our department. We would like to emphasise the benefits and effectiveness of this multimodal, patient-centre and evidence-based ERAS. This, perhaps, should be the standard of care for all patients who undergo microvascular breast reconstruction in the future.

Metaplastic Breast Cancer Masquerading as Liposarcoma of the Breast: A Case Report following Oncoplastic Treatment.

Mammary liposarcoma is among the rarest of breast tumours. Here we report the presentation, macroscopic, microscopic, and immunohistochemical features of an extremely rare case of metaplastic carcinoma with extensive pleomorphic liposarcomatous differentiation. A 47-year-old woman presented with bilateral grade III breast ptosis and a 3 × 4 cm mass in the lower outer quadrant of the left breast. Mammography and ultrasound confirmed a well-defined mass. A core biopsy performed was diagnosed as pleomorphic liposarcoma. Microscopically, this was a well-defined, lobulated tumour comprising solid sheets of large pleomorphic and spindle cells with bizarre forms, vacuolated cytoplasm, and ample mitoses. Atypical lipoblasts were easily identifiable. Due to the strong, though patchy, cytokeratin expression, the diagnosis of metaplastic carcinoma with pleomorphic liposarcomatous differentiation was made. Extensive sampling, careful search for a biphasic pattern, ductal carcinoma in situ, and/or epithelial differentiation, and a panel of broad-spectrum cytokeratins are essential to establish the diagnosis.

Mastectomy scars following breast reconstruction: should routine histologic analysis be performed?

BACKGROUND: There is some debate in the recent literature regarding the routine submission of mastectomy scars for histologic analysis when performing delayed breast reconstructions. The aim of this study was to review the relevant publications and evaluate the practice of routine histologic examination of mastectomy scars. METHODS: The authors conducted a retrospective review, across three regional plastic and reconstructive surgery units, of 433 patients who had 455 scars routinely sent for histologic examination following delayed breast reconstruction between January of 2000 and December of 2006. Patients with clinical evidence of recurrent carcinoma were excluded. RESULTS: Data from 433 patients revealed an average age at reconstruction of 49.9 years (range, 25 to 77 years). The mean interval from primary breast surgery to reconstruction was 3.9 years (range, 2 months to 32 years), and the average length of patient follow-up, from primary surgery, was 6.4 years (range, 1 to 40 years). The majority of the initial operations were carried out for invasive carcinoma (89 percent). Four mastectomy scars in three patients were positive for carcinoma recurrence. CONCLUSIONS: The publications related to the practice of routine histologic analysis of mastectomy scars provide conflicting conclusions. As a proportion of patients may benefit from the early detection and treatment of locoregional recurrence, the authors suggest that the routine submission of mastectomy scars will allow for the earlier detection of soft-tissue recurrences that may affect long-term outcome. In keeping with cancer surgery principles, the authors recommend routine histologic examination of mastectomy scars following delayed breast reconstruction.

Hypospadias surgery in plastic surgery: a snapshot of today with an eye on tomorrow.

The current provision of hypospadias correctional surgery lies across the specialities of paediatric surgery, general surgery, urology and plastic surgery. This study aimed to look at how this provision is structured within plastic surgery, what plastic surgeons are currently doing and how this impacts on training. All plastic surgery units within the UK were contacted via letter and telephone in order to ascertain their current practice with regard to hypospadias surgery. Specialist registrars in the West Midlands Deanery were also questioned on their training in this area. The results indicate that 42 plastic surgeons in the UK carry out hypospadias surgery. The majority of clinicians use the Bracka two-stage repair (88%), with Snodgrass (45%) and MAGPI (43%) widely used. Operations are being carried out across the age spectrum from birth, with 51% favouring intervention at 3 years or more. Approximately two-thirds of plastic surgeons treat less than 25 patients per year. One-third treat 26 to 50, with only two clinicians claiming to treat more than 50 patients per year. Of the specialist registrars questioned in the West Midlands Deanery the majority (74%) were confident with the assessment of new cases and in obtaining consent. One-quarter of registrars (28%) only wished to carry out hypospadias surgery once they were consultants, with only one feeling that they had the necessary training to achieve this now. Plastic surgeons represent about half (52%) of the consultants currently identified in the UK as carrying out hypospadias surgery. If this provision is to be maintained then a greater opportunity for development of skills and experience needs to be created within plastic surgery training. The authors advocate the formulation of a coordinated national framework for the provision of this service, promoting a regional focus for skills and governance.

Treacher Collins syndrome: an undescribed characteristic of the condition and its management with botulinum toxin and surgery.

Mandibulofacial dysostosis (Treacher Collins syndrome) is associated with clinical abnormalities of structures derived from the first and second branchial arches, including antimongoloid slant of palpebral fissures, colobomas of the lower eyelid, eyelash malformations, and malar and mandibular defects. We describe an unusual clinical feature associated with colobomas of the lower eyelids, in a patient with mandibulofacial dysostosis, successfully treated with botulinum toxin and subsequent surgery.

Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737.

ABT-737 is a novel and potent Bcl-2 antagonist with single-agent activity against small-cell lung cancer (SCLC) cell lines. Here, we evaluated the contribution of Bcl-2 family members to the in vitro cellular response of several SCLC cell lines to ABT-737. Relatively higher levels of Bcl-2, Bcl-X(L), Bim and Noxa, and lower levels of Mcl-1 characterized naïve SCLC cell lines that were sensitive to ABT-737. Conversely, a progressive decrease in the relative levels of Bcl-2 and Noxa and a progressive increase in Mcl-1 levels characterized the increased resistance of H146 cells following chronic exposure to ABT-737. Knockdown of Mcl-1 with small interfering RNA sensitized two resistant SCLC cell lines H196 and DMS114 to ABT-737 by enhancing the induction of apoptosis. Likewise, up-regulation of Noxa sensitized H196 cells to ABT-737. Combination treatment with DNA-damaging agents was extremely synergistic with ABT-737 and was associated with the down-regulation of Mcl-1 and the up-regulation of Noxa, Puma, and Bim in H196 cells. Thus, SCLC cells sensitive to ABT-737 expressed the target proteins Bcl-2 and Bcl-X(L), whereas Mcl-1 and factors regulating Mcl-1 function seem to contribute to the overall resistance of SCLC cells to ABT-737. Overall, these observations provide further insight as to the mechanistic bases for ABT-737 efficacy in SCLC and will be helpful for profiling patients and aiding in the rational design of combination therapies.

A small-molecule inhibitor of Bcl-XL potentiates the activity of cytotoxic drugs in vitro and in vivo.

Inhibition of the prosurvival members of the Bcl-2 family of proteins represents an attractive strategy for the treatment of cancer. We have previously reported the activity of ABT-737, a potent inhibitor of Bcl-2, Bcl-X(L), and Bcl-w, which exhibits monotherapy efficacy in xenograft models of small-cell lung cancer and lymphoma and potentiates the activity of numerous cytotoxic agents. Here we describe the biological activity of A-385358, a small molecule with relative selectivity for binding to Bcl-X(L) versus Bcl-2 (K(i)'s of 0.80 and 67 nmol/L for Bcl-X(L) and Bcl-2, respectively). This compound efficiently enters cells and co-localizes with the mitochondrial membrane. Although A-385358 shows relatively modest single-agent cytotoxic activity against most tumor cell lines, it has an EC(50) of <500 nmol/L in cells dependent on Bcl-X(L) for survival. In addition, A-385358 enhances the in vitro cytotoxic activity of numerous chemotherapeutic agents (paclitaxel, etoposide, cisplatin, and doxorubicin) in several tumor cell lines. In A549 non-small-cell lung cancer cells, A-385358 potentiates the activity of paclitaxel by as much as 25-fold. Importantly, A-385358 also potentiated the activity of paclitaxel in vivo. Significant inhibition of tumor growth was observed when A-385358 was added to maximally tolerated or half maximally tolerated doses of paclitaxel in the A549 xenograft model. In tumors, the combination therapy also resulted in a significant increase in mitotic arrest followed by apoptosis relative to paclitaxel monotherapy.

Biological activity of A-289099: an orally active tubulin-binding indolyloxazoline derivative.

In this report, we describe the antitumor activity of A-289099, an indolyloxazoline derivative with antimitotic activity. A-289099 decreased the proliferation of a variety of cells with EC(50) values ranging from 5.1 to 12.8 nM in a P-glycoprotein-independent manner. In cultured cells, microtubules depolymerized in a time- and dose-dependent manner when treated with A-289099. In competition-binding assays, A-298099 competed with [(3)H]colchicine for binding to tubulin (K(i) = 0.65 micro M); however, it did not compete with [(3)H]paclitaxel or [(3)H]vincristine. There was an accumulation of cells in G(2)-M after treatment with A-289099 for 8 h and a subsequent increase in a subdiploid population and an increase in caspase-3 activity, indicative of apoptosis after treatment for 24 and 48 h. The antitumor activities of A-289099 were evaluated using the syngeneic M5076 murine reticulum sarcoma flank tumor model. Animals size-matched for established tumors ( approximately 350 mm(3)) were dosed p.o. (50 mg/kg every day) for 11 days starting on day 10 postinoculation. Tumors from A-289099-treated animals regressed throughout the 11-day dosing period with a percentage of the average treated-tumor-volume divided by the average vehicle-control-tumor-volume (% T/C) value of 11% after treatment for 7 days. Examination of tumor sections revealed an increase in internucleosomal DNA fragmentation or cell death within the central core after drug-treatment. A decrease in the perfusion of tumors was observed after drug-treatment that was localized primarily to the central core and closely associated with the regions of cell death. In summary, our findings indicate A-289099 is a promising, orally active tubulin-binding compound with antitumor activity in vivo.

Potent, orally active heterocycle-based combretastatin A-4 analogues: synthesis, structure-activity relationship, pharmacokinetics, and in vivo antitumor activity evaluation.

The synthesis and structure-activity relationship study of a series of compounds with heterocycles in place of the cis double bond in combretastatin A-4 (CA-4) are described. Substituted tosylmethyl isocyanides were found to be the key intermediates in construction of the heterocycles. Cytotoxicities of the heterocycle-based CA-4 analogues were evaluated against NCI-H460 and HCT-15 cancer cell lines. 3-Amino-4-methoxyphenyl and N-methyl-indol-5-yl were the best replacements for the 3-hydroxy-4-methoxyphenyl in CA-4. 4,5-Disubstituted imidazole was found to be the best for the replacement of the cis double bond in CA-4. Medicinal chemistry efforts led to the discovery of compounds 24h and 25f that were found to be 32 and 82% bioavailable, respectively, in rat. Evaluation of 24h and 25f against murine M5076 reticulum sarcoma in mice revealed that both compounds were orally efficacious with an increase in life span of 38.5 and 40.5%, respectively.

Synthesis and biological evaluation of 2-indolyloxazolines as a new class of tubulin polymerization inhibitors. Discovery of A-289099 as an orally active antitumor agent.

A series of indole containing oxazolines has been discovered as a result of structural modifications of the lead compound A-105972. The compounds exert their anticancer activity through inhibition of tubulin polymerization by binding at the colchicine site. A-289099 was identified as an orally active antimitotic agent active against various cancer cell lines including those that express the MDR phenotype. The anticancer activity, pharmacokinetics, and an efficient and enantioselective synthesis of A-289099 are described.