Defining Benchmarks for Pelvic Exenteration Surgery: A Multicentre Analysis of Patients with Locally Advanced and Recurrent Rectal Cancer.

OBJECTIVE: To establish globally applicable benchmark outcomes for pelvic exenteration (PE) in patients with locally advanced primary (LARC) and recurrent rectal cancer (LRRC), using outcomes achieved at highly specialised centres. BACKGROUND DATA: PE is established as the standard of care for selected patients with LARC and LRRC. There are currently no available benchmarks against which surgical performance in PE can be compared for audit and quality improvement. METHODS: This international multicentre retrospective cohort study included patients undergoing PE for LARC or LRRC at 16 highly experienced centres between 2018 and 2023. Ten outcome benchmarks were established in a lower-risk subgroup. Benchmarks were defined by the 75th percentile of the results achieved at the individual centres. RESULTS: 763 patients underwent PE, of which 464 patients (61%) had LARC and 299 (39%) had LRRC. 544 patients (71%) who met predefined lower risk criteria formed the benchmark cohort. For LARC patients, the calculated benchmark threshold for major complication rate was ≤44%; comprehensive complication index (CCI): ≤30.2; 30-day mortality rate: 0%; 90-day mortality rate: ≤4.3%; R0 resection rate: ≥79%. For LRRC patients, the calculated benchmark threshold for major complication rate was ≤53%; CCI: ≤34.1; 30-day mortality rate: 0%; 90-day mortality rate: ≤6%; R0 resection rate: ≥77%. CONCLUSIONS: The reported benchmarks for PE in patients with LARC and LRRC represent the best available care for this patient group globally and can be used for rigorous assessment of surgical quality and to facilitate quality improvement initiatives at international exenteration centres.

If speed is of the essence: rapid analysis of ambergris by APCI compact mass spectrometry.

The use of atmospheric pressure chemical ionisation (APCI) compact mass spectrometry (CMS) was investigated for the analysis of jetsam and museum-archived ambergris and of ambergris components in perfumes. The data were compared with those from existing methods. Authentic samples of some individual ambergris constituents (ambrein, coprostanol, epicoprostanol and coprostanone), were also examined. Rapid APCI CMS was achieved using either a solids probe or a probe with solutions held in capillary melting point tubes. Interpretation is made of the spectra of the principal natural product components, the relative ion responses were measured and the elemental composition of key ions in the spectra confirmed using high resolution accurate mass APCI MS. Rapid analysis of ambergris by APCI CMS may prove to be a further convenient method of identifying ambrein, of measuring the relative ratios of ambrein and steroids in ambergris and even of quantifying the latter, with minimal sample preparation.

Variation in outcome measurement and reporting in studies of pelvic exenteration for locally advanced and recurrent rectal cancer: a systematic review.

AIM: There is increasing research interest in pelvic exenteration for locally advanced and recurrent rectal cancer. Heterogeneity in outcome reporting can prevent meaningful interpretation and valid synthesis of pooled data and meta-analyses. The aim of this study was to assess homogeneity in outcome measures in the current pelvic exenteration literature. METHOD: MEDLINE, Embase, CENTRAL, CINAHL and Scopus databases were searched from 1990 to 25 April 2023 to identify studies reporting outcomes of pelvic exenteration for locally advanced or recurrent rectal cancer. All reported outcomes were extracted, merged with those of similar meaning and assigned a domain. RESULTS: Of 4137 abstracts screened, 156 studies met the inclusion criteria. A total of 2765 outcomes were reported, of which 17% were accompanied by a definition. There were 1157 unique outcomes, merged into 84 standardized outcomes and assigned one of seven domains. The most reported domains were complications (147 studies, 94%), survival (127, 81%) and surgical outcomes (123, 79%). Resection margins were reported in 122 studies (78%): the definition of a clear resection margin was not provided in 45 studies (37%), it was unclear in 11 studies (9%) and not specified beyond microscopically 'clear' or 'negative' in 31 (28%). Measurements of 2, 1, 0.5 mm and any healthy tissue were all used to define R0 margins. CONCLUSION: There is significant heterogeneity in outcome measurement and reporting in the current pelvic exenteration literature, raising concerns about the validity of comparative or collaborative studies between centres and meta-analyses. Coordinated international collaboration is required to define core outcome sets and benchmarks.

Patients Undergoing Systemic Anti-Cancer Therapy Who Require Surgical Intervention: What Surgeons Need to Know.

As part of routine cancer care, patients may undergo elective surgery with the aim of long-term cure. Some of these patients will receive systemic anti-cancer therapy (SACT) in the neoadjuvant and adjuvant settings. The majority of patients, usually with locally advanced or metastatic disease, will receive SACT with palliative intent. These treatment options are expanding beyond traditional chemotherapy to include targeted therapies, immunotherapy, hormone therapy, radionuclide therapy and gene therapy. During treatment, some patients will require surgical intervention on an urgent or emergency basis. This narrative review examined the evidence base for SACT-associated surgical risk and the precautions that a surgical team should consider in patients undergoing SACT.

Fluorescence-guided surgery: comprehensive review.

BACKGROUND: Despite significant improvements in preoperative workup and surgical planning, surgeons often rely on their eyes and hands during surgery. Although this can be sufficient in some patients, intraoperative guidance is highly desirable. Near-infrared fluorescence has been advocated as a potential technique to guide surgeons during surgery. METHODS: A literature search was conducted to identify relevant articles for fluorescence-guided surgery. The literature search was performed using Medical Subject Headings on PubMed for articles in English until November 2022 and a narrative review undertaken. RESULTS: The use of invisible light, enabling real-time imaging, superior penetration depth, and the possibility to use targeted imaging agents, makes this optical imaging technique increasingly popular. Four main indications are described in this review: tissue perfusion, lymph node assessment, anatomy of vital structures, and tumour tissue imaging. Furthermore, this review provides an overview of future opportunities in the field of fluorescence-guided surgery. CONCLUSION: Fluorescence-guided surgery has proven to be a widely innovative technique applicable in many fields of surgery. The potential indications for its use are diverse and can be combined. The big challenge for the future will be in bringing experimental fluorophores and conjugates through trials and into clinical practice, as well as validation of computer visualization with large data sets. This will require collaborative surgical groups focusing on utility, efficacy, and outcomes for these techniques.

Characterizations and comparison of low sulfur fuel oils compliant with 2020 global sulfur cap regulation for international shipping.

The International Marine Organization 2020 Global Sulfur Cap requires ships to burn fuels with <0.50% S and some countries require <0.10% S in certain Sulfur Emission Control Areas but little is known about these new types of fuels. Using both traditional GC-MS and more advanced chromatographic and mass spectrometry techniques, plus stable isotopic, δ13C and δ2H, analyses of pristane, phytane and n-alkanes, the organic components of a suite of three 0.50% S and three 0.10% S compliant fuels were characterized. Two oils were found to be near identical but all of the remaining oils could be forensically distinguished by comparison of their molecular biomarkers and by the profiles of the heterocyclic parent and alkylated homologues. Oils could also be differentiated by their δ13C and δ2H of n-alkanes and isoprenoids. This study provides important forensic data that may prove invaluable in the event of future oil spills.

Long-term surgical complications following pelvic exenteration: Operative management of the empty pelvis syndrome.

AIM: Pelvic exenteration (PE) has become the standard of care for locally advanced and recurrent rectal cancer. The high short-term morbidity reported from this procedure is well established; however, longer term complications of such radical surgery and their management have not been fully addressed. This study aimed to investigate the incidence, indications and outcomes of long-term (more than 90-day) reoperative surgery in this group of patients, with a focus on the empty pelvis syndrome (EPS). METHODS: Clinical data were extracted from a prospectively maintained database, with additional data pertaining to indications, operative details and outcomes of reoperative surgery obtained from electronic medical records. Patients were excluded if reoperative surgery was endoscopic or radiologically guided, was for the investigation or treatment of recurrent disease, or was clearly unrelated to previous surgery. RESULTS: Of 716 patients who underwent PE, 75 (11%) required 101 reoperative abdominal or perineal procedures, 52 (51%) of which were in 40 (6%) patients for complications of EPS. This group were more likely to have undergone a total PE (65% vs. 43%; P < 0.01) with either major bony (70% vs. 50%; P < 0.01) and/or nerve (40% vs. 25%; P = 0.03) resections at index exenteration. The patho-anatomy, surgical management and outcomes of these patients are described herein, considering separately complications of entero-cutaneous fistula, entero-perineal fistula, small bowel obstruction and local management of perineal wound complications. CONCLUSION: Six per cent of PE patients will require re-intervention for the management of EPS. Reliable strategies for preventing EPS remain elusive; however, surgical management is feasible with acceptable short-term outcomes with the optimum strategy to be selected on an individual patient basis.

MV Wakashio grounding incident in Mauritius 2020: The world's first major spillage of Very Low Sulfur Fuel Oil.

Very Low Sulfur Fuel Oils (VSLFO, <0.5% S) are a new class of marine fuel oils, introduced to meet recent International Maritime Organization regulations. The MV Wakashio was reported to have released 1000 t of VLSFO when it grounded on a reef in Mauritius on 25th July 2020. A field sample of oily residue contaminating the Mauritian coast was collected on 16th August 2020 and compared with the Wakashio fuel oil. Both oils were analyzed for organic and elemental content, and stable isotope ratios δ13C and δ2H measured. Comprehensive two-dimensional gas chromatography with high-resolution mass spectrometry was used to identify and compare biomarkers resistant to weathering. The aromatic content in the VLSFO was relatively low suggesting that the potential for ecosystem harm arising from exposure to toxic components may be less than with traditional fuel oil spills. The Wakashio oil spill is, to our knowledge, the first documented spill involving VLSFO.

Biosynthesis of ambrein in ambergris: evidence from isotopic data and identification of possible intermediates.

Ambrein is found in ambergris, a coprolith occurring in the rectum of the sperm whale. In vitro, ambrein is produced by enzymatic cyclisation of squalene, via a monocyclic intermediate. However, little is known of the in vivo process. In order to find evidence for the reaction in vivo, a comparison was made of the δ13C relative isotopic ratios of ambrein in ambergris with those of co-occurring sterols. A statistically significant difference was noted. This suggests that ambrein originates via a different biosynthetic mechanism from that of the sterols. Examination of the minor constituents of a hydrogenolysed extract of ambergris revealed compounds with a bicyclic polypodane nucleus, rather than those with monocyclic structures. It is hypothesised that in vivo biosynthesis of ambrein proceeds, at least in some cases, via bacterial production of bicyclic polypodenols. The latter are known products of non-concerted squalene (or squalene oxide) cyclisations in other organisms.

Ambrein: a minor, but common constituent of mammalian faeces?

For nearly 200 years, the only natural source of the alcohol ambrein has been coproliths produced in about 1% of sperm whales and in related jetsam. However, the finding of ambrein in adipocere/faeces of human corpses, led us to hypothesise that ambrein might occur in the faeces of other mammals. Herein, we used a recently developed gas chromatography-mass spectrometry method, with suitable derivatisation of the hindered hydroxy group of ambrein, to screen a number of extracts of mammalian faeces. Minor proportions of ambrein were detected in digested human sewage sludge and in the dung of elephant, domestic cattle, giraffe and buffalo. Whether ambrein formation in the terrestrial species is associated with coprolith formation, is unknown, but solid deposits known as enteroliths and fecaliths occur in humans and some domestic animals.

Critical considerations for targeting colorectal liver metastases with nanotechnology.

Colorectal cancer remains a significant cause of morbidity and mortality worldwide. Half of all patients develop liver metastases, presenting unique challenges for their treatment. The shortcomings of conventional chemotherapy has encouraged the use of nanomedicines; the application of nanotechnology in the diagnosis and treatment of disease. In spite of technological improvements in nanotechnology, the complexity of biological systems hinders the prospect of nanomedicines being applied in cancer therapy at the present time. This review highlights current biological barriers and discusses aspects of tumor biology together with the physicochemical features of the nanocarrier, that need to be considered in order to develop effective nanotherapeutics for colorectal cancer patients with liver metastases. It becomes clear that incorporating an interdisciplinary approach when developing nanomedicines should assure appropriate disease-driven design and that this will form a critical step in improving their clinical translation. This article is characterized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Volatile and semi-volatile components of jetsam ambergris.

Volatile and semi-volatile compounds account for the odors, long valued in the perfumery industry, of the natural product, ambergris. Here we demonstrate application of solid phase micro extraction (SPME) and gas chromatography-mass spectrometry (GC-MS) to headspace analysis of the volatiles and semi-volatiles of jetsam ambergris. The samples collected in 2017/2018, ranged from a black, sticky material from New Zealand, likely recently ejected from a sperm whale, to a white solid found on a beach in Chile and radiocarbon-dated previously to be about 1000 years old. The traces of volatile/semi-volatile compounds extracted included, odorous γ-dihydroionone and odor-free pristane (2,6,10,14-tetramethylpentadecane), as the major constituents. The ratios of these to one another and to many other minor constituents, varied, depending on sample color and age.

Correction: The Nrf2 inhibitor brusatol is a potent antitumour agent in an orthotopic mouse model of colorectal cancer.

[This corrects the article DOI: 10.18632/oncotarget.25497.].

Development of an orthotopic syngeneic murine model of colorectal cancer for use in translational research.

Improving outcomes in colorectal cancer requires more accurate in vivo modelling of the disease in humans, allowing more reliable pre-clinical assessment of potential therapies. Novel imaging techniques are necessary to improve the longitudinal assessment of disease burden in these models, reducing the number of animals required for translational studies. This report describes the development of an immune-competent syngeneic orthotopic murine model of colorectal cancer, utilising caecal implantation of CT26 cells stably transfected with the luciferase gene into immune-competent BALB/c mice, allowing serial bioluminescent imaging of cancer progression. Luminescence in the stably transfected CT26 cell line, after pre-conditioning in the flank of a BALB/c mouse, accurately reflected cell viability and resulted in primary caecal tumours in five of eight (63%) mice in the initial pilot study following caecal injection. Luminescent signal continued to increase throughout the study period with one mouse (20%) developing a liver metastasis. Histopathological assessment confirmed tumours to be consistent with a poorly differentiated adenocarcinoma. We have now performed this technique in 68 immune-competent BALB/c mice. There have been no complications from the procedure or peri-operative deaths, with primary tumours developing in 44 (65%) mice and liver metastases in nine (20%) of these. This technique provides an accurate model of colorectal cancer with tumours developing in the correct microenvironment and metastasising to the liver with a similar frequency to that seen in patients presenting with colorectal cancer, with serial bioluminescent reducing the murine numbers required in studies by removing the need for cull for assessment of disease burden.

The Nrf2 inhibitor brusatol is a potent antitumour agent in an orthotopic mouse model of colorectal cancer.

Nrf2 is a transcription factor that regulates cellular stress response and irinotecan-metabolising pathways. Its aberrant activity has been reported in a number of cancers, although relatively few studies have explored a role for Nrf2 in colorectal cancer (CRC). This study assessed the expression of Nrf2 in patient CRC tissues and explored the effect of Nrf2 modulation alone, or in combination with irinotecan, in human (HCT116) and murine (CT26) cell lines in vitro and in an orthotopic syngeneic mouse model utilising bioluminescent imaging. Using a tissue microarray, Nrf2 was found to be overexpressed (p<0.01) in primary CRC and metastatic tissue relative to normal colon, with a positive correlation between Nrf2 expression in matched primary and metastatic samples. In vitro experiments in CRC cell lines revealed that Nrf2 siRNA and brusatol, which is known to inhibit Nrf2, decreased viability and sensitised cells to irinotecan toxicity. Furthermore, brusatol effectively abrogated CRC tumour growth in subcutaneously and orthotopically-allografted mice, resulting in an average 8-fold reduction in luminescence at the study end-point (p=0.02). Our results highlight Nrf2 as a promising drug target in the treatment of CRC.

Further spectral and chromatographic studies of ambergris.

Jetsam ambergris, found washed ashore on beaches, is an environmentally modified form of a natural product of Sperm whales which sometimes develops a pleasant odour. Odorous samples have proved valuable in perfumery. Identification of jetsam ambergris by analysis of organic-soluble extracts by Fourier transform infra-red spectroscopy (FTIR) and of derivatised samples by gas chromatography-mass spectrometry (GC-MS) has already been shown. Here, we describe a different method, in which characteristic alkenic protons and carbon atoms of the major constituent ambrein, were identified in whole extracts using nuclear magnetic resonance spectroscopy (NMR). The advantages of employing NMR spectroscopy included rapidity, reduced losses of volatiles compared to GC-MS and detection of non-GC amenable constituents. However, the identities and quantities of co-occurring individual components (e.g. steroids) could not easily be assigned in the unfractionated extracts by NMR spectroscopy, whereas they were by GC-MS, so an approach combining FTIR, GC-MS and NMR spectroscopic methods is advocated.