Visualising cancer in 3D: 3-Dimensional Tissue Imaging for management of cutaneous basal cell carcinoma.

Surgical management of basal cell carcinoma (BCC) typically involves surgical excision with post-operative margin assessment using the bread-loafing technique; or gold-standard Mohs micrographic surgery (MMS), where margins are iteratively examined for residual cancer after tumour removal, with additional excisions performed upon detecting residual tumour at margins. There is limited sampling of resection margins with bread loafing, with detection of positive margins 44% of the time using 2 mm intervals. To resolve this, we have developed three-dimensional (3D) Tissue Imaging for: (1) complete examination of cancer margins and (2) detection of tumour proximity to nerves and blood vessels. 3D Tissue optical clearing with a light sheet imaging protocol was developed for margin assessment in two datasets assessed by two independent evaluators: (1) 48 samples from 29 patients with varied BCC subtypes, sizes and pigmentation levels; (2) 32 samples with matching Mohs' surgeon reading of tumour margins using two-dimensional haematoxylin & eosin-stained sections. The 3D Tissue Imaging protocol permits a complete examination of deeper and peripheral margins. Two independent evaluators achieved negative predictive values of 92.3% and 88.24% with 3D Tissue Imaging. Images obtained from 3D Tissue Imaging recapitulates histological features of BCC, such as nuclear crowding, palisading and retraction clefting and provides a 3D context for recognising normal skin adnexal structures. Concurrent immunofluorescence labelling of nerves and blood vessels allows visualisation of structures closer to tumour-positive regions, which may have a higher risk for neural and vascular infiltration. Together, this method provides more information in a 3D spatial context, enabling better cancer management by clinicians.

A prospective study evaluating patient reported outcome measures in patients who have undergone chest wall perforator flaps.

AIMS: To evaluate Patient Reported Outcome Measures (PROMs) and surgical outcomes in patients undergoing Chest Wall Perforator Flaps (CWPFs). METHODS: This was an observational single cohort study using an audit approach and a survey instrument. 84 patients who had undergone CWPFs in the last 5 years at the Department of Breast Surgery, City Hospital Birmingham, were identified from a pre-existing database. Surgical outcomes were recorded. Patients were contacted telephonically or in person at the time of follow-up and were asked to fill up a PROMs questionnaire. RESULTS: Out of 84 patients, 58 patients chose to respond. The average age of the patients was 51.3 years (±8.2 years). The average follow-up was 15.4 months (±9.9 months). The most common histological subtype was Infiltrating ductal carcinoma (IDC)-Not otherwise specified 34/58 (58.6%). Majority of the patients had T2 cancers-28/58 (48.3%). 26/58 (44.8%) were node negative. Eight patients (13.7%) had post-operative complications. No patient had total/partial flap loss. Nine patients (15.5%) had margin re-excision. One patient developed distant metastasis while 1 patient developed a second primary. Fifty-one patients (88%) were either satisfied or very satisfied with the post-operative appearance of the breasts. Thirty-six patients (62%) had no/little persistent pain or tenderness post-surgery. Eighty-six per cent (38/44) of the patients undergoing Lateral Intercostal Artery Perforator (LICAP) Flap and 16/18 (89%) of patients undergoing Anterior Intercostal Artery Perforator (AICAP) flap had no/little difficulty in carrying out normal activities at follow up. CONCLUSION: CWPFs are associated with a low complication rate and a high patient satisfaction rate.

Pushing the Boundaries of Pedicled Chest Wall Perforator Flaps in Oncoplastic Breast Surgery.

Among 145 chest wall perforator flaps (CWPFs) performed at City Hospital, Birmingham (September 2017-February 2022), 11 were for novel indications, four were for whole breast reconstructions, two were for implant salvage procedures, three were CWPFs with skin paddle to replace excised skin/nipple-areola complex, and two were for upper inner quadrant tumours. Tumour characteristics and post-operative complications were noted. Patient-reported outcomes measures (PROMs) were measured using a questionnaire adapted from the National Mastectomy and Breast Reconstruction Audit (NMBRA) study. Among 11 patients, nine (81.81%) did not develop any complications. Ten patients responded to PROMs (median follow-up of eight months). The PROMs assessment showed that all patients (100%) were satisfied with the post-operative breast appearance. Of the patients, 90% (9/10) felt the results of their surgery to be good, very good, or excellent. Of the patients, 70% (7/10) said that they have no/little persistent pain. None of the patients had difficulty carrying out normal activities. Thus, the applications of CWPFs could be extended for whole breast reconstruction, implant salvage procedures, where skin paddle is needed, and for upper inner quadrant tumours.

Nickel-Catalyzed Sulfonylation of Aryl Bromides Enabled by Potassium Metabisulfite as a Uniquely Effective SO2 Surrogate.

The development and mechanistic investigation of a nickel-catalyzed sulfonylation of aryl bromides is disclosed. The reaction proceeds in good yields for a variety of substrates and utilizes an inexpensive, stench-free, inorganic sulfur salt (K2 S2 O5 ) as a uniquely effective SO2 surrogate. The active oxidative addition complex was synthesized, isolated, and fully characterized by a combination of NMR spectroscopy and X-ray crystallography analysis. The use of the isolated oxidative addition complex in both stoichiometric and catalytic reactions revealed that SO2 insertion occurs via dissolved SO2 , likely released upon thermal decomposition of K2 S2 O5 . Key to the success of the reaction is the role of K2 S2 O5 as a reservoir of SO2 that is slowly released, thus preventing catalyst poisoning.

A Study Protocol of Realist Evaluation of Palliative Home Care Program for Non-Cancer Patients in Singapore.

Introduction: Violet Program (ViP) was developed to address the current home palliative service gap for individuals with life limiting non-cancer conditions residing in the Eastern part of Singapore. While its basic principles and processes have been planned and implemented, how ViP works, for whom and in what circumstances are not yet well understood. Therefore, we propose for a realist evaluation (RE) - a theory-based evaluation, to address the current knowledge gaps. Evaluation findings may guide, support further development and broader uptake of ViP. Methods and Analysis: This study will be conducted in three phases: 1. development of initial program theory (IPT), 2. testing of programme theory, and 3. refinement of IPT. First, IPT will be elicited through review of programme documents, scoping review of reviews and in-depth interviews with stakeholders involved in the conceptualization of ViP. Then, a convergent mixed method study will be conducted to assess contexts (C), mechanisms (M) and outcomes (O) to test the IPT through interviews with stakeholders, surveys and analysis of program and administrative databases. Based on findings gathered and through consultation with respective stakeholders, IPT will be refined to highlight what works (outcomes), how (mechanisms) and for whom under what conditions (contexts).

Chyle Leak After Axillary Node Clearance in Breast Cancer Surgery-A Rare Complication and a Proposed Management Strategy from the British and Italian Experience.

BACKGROUND: Chyle leak after axillary surgery is a rare complication that lacks consensus and management guidelines. This study aimed to present the experiences of two centers in chyle leak management after axillary node clearance for breast cancer. Furthermore the authors provide a review of its pathophysiology and clinical diagnostic methods. They compare approaches for management of the axilla with those for other locations. METHODS: A multicentre case series descriptive analysis of chyle leak after breast cancer axillary node clearance between 1 January 2013 and 31 May 2020 was performed. RESULTS: The center in the United Kingdom and the center in Italy performed 655 and 4969 axillary node clearances, respectively. Four patients experienced chyle leaks. All the leaks had left-sided surgery (3 patients had level 3 clearances with mastectomy and implant-based breast reconstructions; 1 patient had level 2 clearance with therapeutic mammoplasty). All the leaks appeared within 3 days after surgery. Leak duration was between 11 and 29 days. The maximum daily output was 600 mL. All the leaks were treated conservatively with nutritional team support together with close drainage monitoring. The management strategy included a low-fat diet, a high-protein diet, total parenteral nutrition, and medium chain triglyceride supplements, as well as other elements. No negative effects on oncoplastic and reconstructive breast surgery wound-healing and no delays in adjuvant treatment were observed. CONCLUSION: The incidence of chyle leak after breast cancer axillary node clearance was 0.07%. Early diagnosis and close monitoring together with conservative management involving nutritional team support can result in successful treatment of chyle leak without negative sequalae of breast cancer oncologic treatment.

Comparison of surgical and oncological outcomes between oncoplastic breast-conserving surgery versus conventional breast-conserving surgery for treatment of breast cancer: A systematic review and meta-analysis of 31 studies.

AIMS: To evaluate comparative outcomes of oncoplastic breast conserving surgery (OBCS) versus conventional breast conserving surgery (BCS) for breast cancer treatment. METHODS: A systematic search of multiple electronic data sources was conducted, and all eligible studies comparing OBCS and BCS were included. Characteristics of the tumour includes preoperative size of tumour on imaging and the weight of the specimen after resection. While positive margins rate, re-excision rate, completion mastectomy rate and loco-regional recurrence were considered as oncological outcome parameters. Post-operative complications include surgical site infection (SSI), seroma, haematoma and skin/nipple necrosis. RESULTS: Thirty-one studies reporting a total number of 115011 patients who underwent OBCS (n = 11978) or BCS (n = 103033) were included. OBCS group showed lower risk of positive margins rate [OR 0.76, P = 0.05], re-excision rate [OR 0.72, P = 0.02], and loco-regional recurrence [OR 0.62, P = 0.03] compared to BCS group. There was no significant difference between the two groups regarding post-operative complications. CONCLUSION: Although there is a lack of level 1 evidence, the available studies clearly demonstrate superior or at least equivalent outcomes when comparing OBCS with conventional BCS. The benefits of OBCS include dealing with larger tumours, wider surgical margins and better aesthetic results for patients.

Surface-engineered extracellular vesicles for targeted delivery of therapeutic RNAs and peptides for cancer therapy.

The advent of novel therapeutics in recent years has urged the need for a safe, non-immunogenic drug delivery vector capable of delivering therapeutic payloads specifically to diseased cells, thereby increasing therapeutic efficacy and reducing side effects. Extracellular vesicles (EVs) have garnered attention in recent years as a potentially ideal vector for drug delivery, taking into account their intrinsic ability to transfer bioactive cargo to recipient cells and their biocompatible nature. However, natural EVs are limited in their therapeutic potential and many challenges need to be overcome before engineered EVs satisfy the levels of efficiency, stability, safety and biocompatibility required for therapeutic use. Here, we demonstrate that an enzyme-mediated surface functionalization method in combination with streptavidin-mediated conjugation results in efficient surface functionalization of EVs. Surface functionalization using the above methods permits the stable and biocompatible conjugation of peptides, single domain antibodies and monoclonal antibodies at high copy number on the EV surface. Functionalized EVs demonstrated increased accumulation in target cells expressing common cancer associated markers such as CXCR4, EGFR and EpCAM both in vitro and in vivo. The functionality of this approach was further highlighted by the ability of targeting EVs to specifically deliver therapeutic antisense oligonucleotides to a metastatic breast tumor model, resulting in increased knockdown of a targeted oncogenic microRNA and improved metastasis suppression. The method was also used to equip EVs with a bifunctional peptide that targets EVs to leukemia cells and induces apoptosis, leading to leukemia suppression. Moreover, we conducted extensive testing to verify the biocompatibility, and safety of engineered EVs for therapeutic use, suggesting that surface modified EVs can be used for repeated dose treatment with no detectable adverse effects. This modular, biocompatible method of EV engineering offers a promising avenue for the targeted delivery of a range of therapeutics while addressing some of the safety concerns associated with EV-based drug delivery.

Primary radiotherapy and deep inferior epigastric perforator flap reconstruction for patients with breast cancer (PRADA): a multicentre, prospective, non-randomised, feasibility study.

BACKGROUND: Radiotherapy before mastectomy and autologous free-flap breast reconstruction can avoid adverse radiation effects on healthy donor tissues and delays to adjuvant radiotherapy. However, evidence for this treatment sequence is sparse. We aimed to explore the feasibility of preoperative radiotherapy followed by skin-sparing mastectomy and deep inferior epigastric perforator (DIEP) flap reconstruction in patients with breast cancer requiring mastectomy. METHODS: We conducted a prospective, non-randomised, feasibility study at two National Health Service trusts in the UK. Eligible patients were women aged older than 18 years with a laboratory diagnosis of primary breast cancer requiring mastectomy and post-mastectomy radiotherapy, who were suitable for DIEP flap reconstruction. Preoperative radiotherapy started 3-4 weeks after neoadjuvant chemotherapy and was delivered to the breast, plus regional nodes as required, at 40 Gy in 15 fractions (over 3 weeks) or 42·72 Gy in 16 fractions (over 3·2 weeks). Adverse skin radiation toxicity was assessed preoperatively using the Radiation Therapy Oncology Group toxicity grading system. Skin-sparing mastectomy and DIEP flap reconstruction were planned for 2-6 weeks after completion of preoperative radiotherapy. The primary endpoint was the proportion of open breast wounds greater than 1 cm width requiring a dressing at 4 weeks after surgery, assessed in all participants. This study is registered with ClinicalTrials.gov, NCT02771938, and is closed to recruitment. FINDINGS: Between Jan 25, 2016, and Dec 11, 2017, 33 patients were enrolled. At 4 weeks after surgery, four (12·1%, 95% CI 3·4-28·2) of 33 patients had an open breast wound greater than 1 cm. One (3%) patient had confluent moist desquamation (grade 3). There were no serious treatment-related adverse events and no treatment-related deaths. INTERPRETATION: Preoperative radiotherapy followed by skin-sparing mastectomy and immediate DIEP flap reconstruction is feasible and technically safe, with rates of breast open wounds similar to those reported with post-mastectomy radiotherapy. A randomised trial comparing preoperative radiotherapy with post-mastectomy radiotherapy is required to precisely determine and compare surgical, oncological, and breast reconstruction outcomes, including quality of life. FUNDING: Cancer Research UK, National Institute for Health Research.

Melanoma in Singapore: A 20-year review of disease and treatment outcomes.

INTRODUCTION: Melanomas in Asians have different clinicopathological characteristics and prognosis from melanomas in Caucasians. This study reviewed the epidemiology and treatment outcomes of cutaneous melanoma diagnosed at a tertiary referral dermatology centre in Singapore, which has a multiracial population. The study also determined whether Asians had comparable relapse-free and overall survival periods to Caucasians in Singapore. METHOD: This is a retrospective review of cutaneous melanoma cases in our centre between 1996 and 2015. RESULTS: Sixty-two cases of melanoma were diagnosed in 61 patients: 72.6% occurred in Chinese, 19.4% in Caucasians and 3.2% in Indians, with an over-representation of Caucasians. Superficial spreading melanoma, acral lentiginous melanoma and nodular melanoma comprised 37.1%, 35.5% and 22.6% of the cases, respectively. The median time interval to diagnosis was longer in Asians than Caucasians; median Breslow's thickness in Asians were significantly thicker than in Caucasians (2.6mm versus 0.9mm, P=0.018) and Asians tend to present at a later stage. The mortality rates for Asians and Caucasians were 52% and 0%, respectively. CONCLUSION: More physician and patient education on skin cancer awareness is needed in our Asian-predominant population for better outcomes.

New approaches in extracellular vesicle engineering for improving the efficacy of anti-cancer therapies.

Cancer is a disease that evolves continuously with unpredictable outcomes. Although conventional chemotherapy can display significant antitumor effects, the lack of specificity and poor bioavailability remain major concerns in cancer therapy. Moreover, with the advent of novel anti-cancer gene therapies, there is an urgent need for drug delivery vectors capable of bypassing cellular barriers and efficiently transferring therapeutic cargo to recipient cells. A number of drug delivery systems have been proposed to overcome these limitations, but their successful clinical translation has been hampered by the onset of unexpected side effects and associated toxicities. The application of extracellular vesicles (EVs), a class of naturally released, cell-derived particles, as drug delivery vectors presents a breakthrough in nanomedicine, taking into account their biocompatibility and natural role in intercellular communication. Combining the advantageous intrinsic properties of EVs with surface functionalization and the encapsulation of drugs allows for a new class of engineered EVs that serve as effective therapeutic carriers. Here, we describe the various successful approaches involving the application of engineered EVs as bio-derived drug delivery vectors in cancer therapy. The latest and most effective strategies of engineering EVs to improve drug loading, stealth properties and tumour targeting capabilities of EVs are debated. Finally, current obstacles and future perspectives of smart engineered EVs are discussed.

Circulating Tumour DNA in Muscle-Invasive Bladder Cancer.

Circulating tumour DNA (ctDNA) is an attractive tool in cancer research, offering many advantages over tissue samples obtained using traditional biopsy methods. There has been increasing interest in its application to muscle-invasive bladder cancer (MIBC), which is recognised to be a heterogeneous disease with overall poor prognosis. Using a range of platforms, studies have shown that ctDNA is detectable in MIBC and may be a useful biomarker in monitoring disease status and guiding treatment decisions in MIBC patients. Currently, with no such predictive or prognostic biomarkers in clinical practice to guide treatment strategy, there is a real unmet need for a personalised medicine approach in MIBC, and ctDNA offers an exciting avenue through which to pursue this goal. In this article, we present an overview of work to date on ctDNA in MIBC, and discuss the inherent challenges present as well as the potential future clinical applications.

Noninvasive real-time characterization of non-melanoma skin cancers with handheld optoacoustic probes.

Currently, imaging technologies that enable dermsurgeons to visualize non-melanoma skin cancers (NMSC) in vivo preoperatively are lacking, resulting in excessive or incomplete removal. Multispectral optoacoustic tomography (MSOT) is a volumetric imaging tool to differentiate tissue chromophores and exogenous contrast agents, based on differences in their spectral signatures and used for high-resolution imaging of functional and molecular contrast at centimeter scale depth. We performed MSOT imaging with two- and three-dimensional handheld scanners on 21 Asian patients with NMSC. The tumors and their oxygenation parameters could be distinguished from normal skin endogenously. The lesion dimensions and depths were extracted from the spectral melanin component with three-dimensional spatial resolution up to 80 µm. The intraclass correlation coefficient correlating tumor dimension measurements between MSOT and ex vivo histology of excised tumors, showed good correlation. Real-time 3D imaging was found to provide information on lesion morphology and its underlying neovasculature, indicators of the tumor's aggressiveness.