Perioperative management and anaesthetic considerations in pelvic exenterations using Delphi methodology: Results from the PelvEx Collaborative

Background: The multidisciplinary perioperative and anaesthetic management of patients undergoing pelvic exenteration is essential for good surgical outcomes. No clear guidelines have been established, and there is wide variation in clinical practice internationally. This consensus statement consolidates clinical experience and best practice collectively, and systematically addresses key domains in the perioperative and anaesthetic management. Methods: The modified Delphi methodology was used to achieve consensus from the PelvEx Collaborative. The process included one round of online questionnaire involving controlled feedback and structured participant response, two rounds of editing, and one round of web-based voting. It was held from December 2019 to February 2020. Consensus was defined as more than 80 per cent agreement, whereas less than 80 per cent agreement indicated low consensus. Results: The final consensus document contained 47 voted statements, across six key domains of perioperative and anaesthetic management in pelvic exenteration, comprising preoperative assessment and preparation, anaesthetic considerations, perioperative management, anticipating possible massive haemorrhage, stress response and postoperative critical care, and pain management. Consensus recommendations were developed, based on consensus agreement achieved on 34 statements. Conclusion: The perioperative and anaesthetic management of patients undergoing pelvic exenteration is best accomplished by a dedicated multidisciplinary team with relevant domain expertise in the setting of a specialized tertiary unit. This consensus statement has addressed key domains within the framework of current perioperative and anaesthetic management among patients undergoing pelvic exenteration, with an international perspective, to guide clinical practice, and has outlined areas for future clinical research

Induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as neoadjuvant treatment for locally recurrent rectal cancer: Study protocol of a multicentre, open-label, parallel-arms, randomized controlled study (PelvEx II)

Background: A resection with clear margins (R0 resection) is the most important prognostic factor in patients with locally recurrent rectal cancer (LRRC). However, this is achieved in only 60 per cent of patients. The aim of this study is to investigate whether the addition of induction chemotherapy to neoadjuvant chemo(re)irradiation improves the R0 resection rate in LRRC. Methods: Thismulticentre, international, open-label, phase III, parallel-arms study will enrol 364 patients with resectable LRRC after previous partial or total mesorectal resection without synchronous distant metastases or recent chemo- and/or radiotherapy treatment. Patients will be randomized to receive either induction chemotherapy (three 3-week cycles of CAPOX (capecitabine, oxaliplatin), four 2- week cycles of FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) or FOLFORI (5-fluorouracil, leucovorin, irinotecan)) followed by neoadjuvant chemoradiotherapy and surgery (experimental arm) or neoadjuvant chemoradiotherapy and surgery alone (control arm). Tumours will be restaged usingMRI and, in the experimental arm, a further cycle of CAPOX or two cycles of FOLFOX/FOLFIRI will be administered before chemoradiotherapy in case of stable or responsive disease. The radiotherapy dose will be 25 × 2.0 Gy or 28 × 1.8Gy in radiotherapy-naive patients, and 15 × 2.0Gy in previously irradiated patients. The concomitant chemotherapy agent will be capecitabine administered twice daily at a dose of 825mg/m2 on radiotherapy days. The primary endpoint of the study is the R0 resection rate. Secondary endpoints are long-termoncological outcomes, radiological and pathological response, toxicity, postoperative complications, costs, and quality of life. Discussion: This trial protocol describes the PelvEx II study. PelvEx II, designed as a multicentre, open-label, phase III, parallel-arms study, is the first randomized study to compare induction chemotherapy followed by neoadjuvant chemo(re)irradiation and surgery with neoadjuvant chemo(re)irradiation and surgery alone in patients with locally recurrent rectal cancer, with the aim of improving the number of R0 resections

Induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as neoadjuvant treatment for locally recurrent rectal cancer: study protocol of a multicentre, open-label, parallel-arms, randomized controlled study (PelvEx II)

Background A resection with clear margins (R0 resection) is the most important prognostic factor in patients with locally recurrent rectal cancer (LRRC). However, this is achieved in only 60 per cent of patients. The aim of this study is to investigate whether the addition of induction chemotherapy to neoadjuvant chemo(re)irradiation improves the R0 resection rate in LRRC. Methods This multicentre, international, open-label, phase III, parallel-arms study will enrol 364 patients with resectable LRRC after previous partial or total mesorectal resection without synchronous distant metastases or recent chemo- and/or radiotherapy treatment. Patients will be randomized to receive either induction chemotherapy (three 3-week cycles of CAPOX (capecitabine, oxaliplatin), four 2-week cycles of FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) or FOLFORI (5-fluorouracil, leucovorin, irinotecan)) followed by neoadjuvant chemoradiotherapy and surgery (experimental arm) or neoadjuvant chemoradiotherapy and surgery alone (control arm). Tumours will be restaged using MRI and, in the experimental arm, a further cycle of CAPOX or two cycles of FOLFOX/FOLFIRI will be administered before chemoradiotherapy in case of stable or responsive disease. The radiotherapy dose will be 25 × 2.0 Gy or 28 × 1.8 Gy in radiotherapy-naive patients, and 15 × 2.0 Gy in previously irradiated patients. The concomitant chemotherapy agent will be capecitabine administered twice daily at a dose of 825 mg/m2 on radiotherapy days. The primary endpoint of the study is the R0 resection rate. Secondary endpoints are long-term oncological outcomes, radiological and pathological response, toxicity, postoperative complications, costs, and quality of life. Discussion This trial protocol describes the PelvEx II study. PelvEx II, designed as a multicentre, open-label, phase III, parallel-arms study, is the first randomized study to compare induction chemotherapy followed by neoadjuvant chemo(re)irradiation and surgery with neoadjuvant chemo(re)irradiation and surgery alone in patients with locally recurrent rectal cancer, with the aim of improving the number of R0 resections

Genetic differentiation and intrinsic genomic features explain variation in recombination hotspots among cocoa tree populations

BackgroundRecombination plays an important evolutionary role by breaking up haplotypes and shuffling genetic variation. This process impacts the ability of selection to eliminate deleterious mutations or increase the frequency of beneficial mutations in a population. To understand the role of recombination generating and maintaining haplotypic variation in a population, we can construct fine-scale recombination maps. Such maps have been used to study a variety of model organisms and proven to be informative of how selection and demographics shape species-wide variation. Here we present a fine-scale recombination map for ten populations of Theobroma cacao - a non-model, long-lived, woody crop. We use this map to elucidate the dynamics of recombination rates in distinct populations of the same species, one of which is domesticated.ResultsMean recombination rates in range between 2.5 and 8.6 cM/Mb for most populations of T. cacao with the exception of the domesticated Criollo (525 cM/Mb) and Guianna, a more recently established population (46.5 cM/Mb). We found little overlap in the location of hotspots of recombination across populations. We also found that hotspot regions contained fewer known retroelement sequences than expected and were overrepresented near transcription start and termination sites. We find mutations in FIGL-1, a protein shown to downregulate cross-over frequency in Arabidopsis, statistically associated to higher recombination rates in domesticated Criollo.ConclusionsWe generated fine-scale recombination maps for ten populations of Theobroma cacao and used them to understand what processes are associated with population-level variation in this species. Our results provide support to the hypothesis of increased recombination rates in domesticated plants (Criollo population). We propose a testable mechanistic hypothesis for the change in recombination rate in domesticated populations in the form of mutations to a previously identified recombination-suppressing protein. Finally, we establish a number of possible correlates of recombination hotspots that help explain general patterns of recombination in this species

Local ancestry analysis reveals genomic convergence in extremophile fishes

The molecular basis of convergent phenotypes is often unknown. However, convergence at a genomic level is predicted when there are large population sizes, gene flow among diverging lineages or strong genetic constraints. We used whole-genome resequencing to investigate genomic convergence in fishes ( Poecilia spp.) that have repeatedly colonized hydrogen sulfide (H2S)-rich environments in Mexico. We identified genomic similarities in both single nucleotide polymorphisms (SNPs) and structural variants (SVs) among independently derived sulfide spring populations, with approximately 1.2% of the genome being shared among sulfidic ecotypes. We compared these convergent genomic regions to candidate genes for H2S adaptation identified from transcriptomic analyses and found that a significant proportion of these candidate genes (8%) were also in regions where sulfidic individuals had similar SNPs, while only 1.7% were in regions where sulfidic individuals had similar SVs. Those candidate genes included genes involved in sulfide detoxification, the electron transport chain (the main toxicity target of H2S) and other processes putatively important for adaptation to sulfidic environments. Regional genomic similarity across independent populations exposed to the same source of selection is consistent with selection on standing variation or introgression of adaptive alleles across divergent lineages. However, combined with previous analyses, our data also support that adaptive changes in mitochondrially encoded subunits arose independently via selection on de novo mutations. Pressing questions remain on what conditions ultimately facilitate the independent rise of adaptive alleles at the same loci in separate populations, and thus, the degree to which evolution is repeatable or predictable. This article is part of the theme issue 'Convergent evolution in the genomics era: new insights and directions'

Local ancestry analysis reveals genomic convergence in extremophile fishes

The molecular basis of convergent phenotypes is often unknown. However, convergence at a genomic level is predicted when there are large population sizes, gene flow among diverging lineages or strong genetic constraints. We used whole-genome resequencing to investigate genomic convergence in fishes ( Poecilia spp.) that have repeatedly colonized hydrogen sulfide (H2S)-rich environments in Mexico. We identified genomic similarities in both single nucleotide polymorphisms (SNPs) and structural variants (SVs) among independently derived sulfide spring populations, with approximately 1.2% of the genome being shared among sulfidic ecotypes. We compared these convergent genomic regions to candidate genes for H2S adaptation identified from transcriptomic analyses and found that a significant proportion of these candidate genes (8%) were also in regions where sulfidic individuals had similar SNPs, while only 1.7% were in regions where sulfidic individuals had similar SVs. Those candidate genes included genes involved in sulfide detoxification, the electron transport chain (the main toxicity target of H2S) and other processes putatively important for adaptation to sulfidic environments. Regional genomic similarity across independent populations exposed to the same source of selection is consistent with selection on standing variation or introgression of adaptive alleles across divergent lineages. However, combined with previous analyses, our data also support that adaptive changes in mitochondrially encoded subunits arose independently via selection on de novo mutations. Pressing questions remain on what conditions ultimately facilitate the independent rise of adaptive alleles at the same loci in separate populations, and thus, the degree to which evolution is repeatable or predictable. This article is part of the theme issue 'Convergent evolution in the genomics era: new insights and directions'

Predicting outcomes of pelvic exenteration using machine learning

Aim: We aim to compare machine learning with neural network performance in predicting R0 resection (R0), length of stay > 14 days (LOS), major complication rates at 30 days postoperatively (COMP) and survival greater than 1 year (SURV) for patients having pelvic exenteration for locally advanced and recurrent rectal cancer. Method: A deep learning computer was built and the programming environment was established. The PelvEx Collaborative database was used which contains anonymized data on patients who underwent pelvic exenteration for locally advanced or locally recurrent colorectal cancer between 2004 and 2014. Logistic regression, a support vector machine and an artificial neural network (ANN) were trained. Twenty per cent of the data were used as a test set for calculating prediction accuracy for R0, LOS, COMP and SURV. Model performance was measured by plotting receiver operating characteristic (ROC) curves and calculating the area under the ROC curve (AUROC). Results: Machine learning models and ANNs were trained on 1147 cases. The AUROC for all outcome predictions ranged from 0.608 to 0.793 indicating modest to moderate predictive ability. The models performed best at predicting LOS > 14 days with an AUROC of 0.793 using preoperative and operative data. Visualized logistic regression model weights indicate a varying impact of variables on the outcome in question. Conclusion: This paper highlights the potential for predictive modelling of large international databases. Current data allow moderate predictive ability of both complex ANNs and more classic methods

Simultaneous pelvic exenteration and liver resection for primary rectal cancer with synchronous liver metastases: results from the PelvEx Collaborative

At presentation, 15-20% of patients with rectal cancer already have synchronous liver metastases. The aim of this study was to determine the surgical and survival outcomes in patients with advanced rectal cancer who underwent combined pelvic exenteration and liver (oligometastatic) resection

Perioperative management and anaesthetic considerations in pelvic exenterations using Delphi methodology:Results from the PelvEx Collaborative

Background: The multidisciplinary perioperative and anaesthetic management of patients undergoing pelvic exenteration is essential for good surgical outcomes. No clear guidelines have been established, and there is wide variation in clinical practice internationally. This consensus statement consolidates clinical experience and best practice collectively, and systematically addresses key domains in the perioperative and anaesthetic management. Methods: The modified Delphi methodology was used to achieve consensus from the PelvEx Collaborative. The process included one round of online questionnaire involving controlled feedback and structured participant response, two rounds of editing, and one round of web-based voting. It was held from December 2019 to February 2020. Consensus was defined as more than 80 per cent agreement, whereas less than 80 per cent agreement indicated low consensus. Results: The final consensus document contained 47 voted statements, across six key domains of perioperative and anaesthetic management in pelvic exenteration, comprising preoperative assessment and preparation, anaesthetic considerations, perioperative management, anticipating possible massive haemorrhage, stress response and postoperative critical care, and pain management. Consensus recommendations were developed, based on consensus agreement achieved on 34 statements. Conclusion: The perioperative and anaesthetic management of patients undergoing pelvic exenteration is best accomplished by a dedicated multidisciplinary team with relevant domain expertise in the setting of a specialized tertiary unit. This consensus statement has addressed key domains within the framework of current perioperative and anaesthetic management among patients undergoing pelvic exenteration, with an international perspective, to guide clinical practice, and has outlined areas for future clinical research.</p