Retroperitoneal liposarcomas are rare tumours that carry a poorer prognosis than their extremity counterparts. Within their subtypes-well differentiated (WDL), dedifferentiated (DDL), myxoid (MLS) and pleomorphic (PLS)-they exhibit a diverse genomic landscape. With recent advances in next generation sequencing, the number of studies exploring this have greatly increased. The recent literature has deepened our understanding of the hallmark MDM2/CDK4 amplification in WDL/DDL and addressed concerns about toxicity and resistance when targeting this. The FUS-DDIT3 fusion gene remains the primary focus of interest in MLS with additional potential targets described. Whole genome sequencing has driven identification of novel genes and pathways implicated in WDL/DDL outside of the classic 12q13-15 amplicon. Due to their rarity; anatomical location and histologic subtype are infrequently mentioned when reporting the results of these studies. Reports can include non-adipogenic or extremity tumours, making it difficult to draw specific retroperitoneal conclusions. This narrative review aims to provide a summary of retroperitoneal liposarcoma genomics and the implications for therapeutic targeting. summary of specific retroperitoneal liposarcoma genomics is lacking in the literature. This would be useful to clinicians and scientists alike, dealing with this specific disease in the era of personalised medicine. Secondly, it is well established that variations in the tumour microenvironment can determine response to therapy. Lastly, RPL carries a poorer prognosis than extremity LS, has a distinct natural history and is managed differently. Methods Search strategy A literature search was conducted using the Embase, MEDLINE, PubMed and Cochrane Library databases. The following keywords were used to perform flexible searches within these databases: 'Retroperitoneal' AND 'sarcoma', 'liposarcoma', 'genomics', 'genetics', 'mutation', and 'genomic therapy.' Only papers published in English were included.

Background: Up to 15 per cent of colorectal cancers present with peritoneal metastases (CPM). Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS + HIPEC) aims to achieve macroscopic tumour resection combined with HIPEC to destroy microscopic disease. CRS + HIPEC is a major operation with significant morbidity and effects on quality of life (QoL). Improving patient selection is crucial to maximize patient outcomes while minimizing morbidity and mortality. The aim of this study was to identify prognostic factors for patients with CPM undergoing CRS + HIPEC. Methods: A systematic search of MEDLINE, Embase and Cochrane Library electronic databases was performed using terms for colorectal cancer, peritoneal metastasis and CRS + HIPEC. Included studies focused on the impact of prognostic factors on overall survival following CRS + HIPEC in patients with CPM. Results: Twenty-four studies described 3128 patients. Obstruction or perforation of the primary tumour (hazard ratio (HR) 2⋅91, 95 per cent c.i. 1⋅5 to 5⋅65), extent of peritoneal metastasis as described by the Peritoneal Carcinomatosis Index (PCI) (per increase of 1 PCI point: HR 1⋅07, 1⋅02 to 1⋅12) and the completeness of cytoreduction (CC score above zero: HR 1⋅75, 1⋅18 to 2⋅59) were associated with reduced overall survival after CRS + HIPEC. Conclusion: Primary tumour obstruction or perforation, PCI score and CC score are valuable prognostic factors in the selection of patients with CPM for CRS + HIPEC.

Radiotherapy is routinely used as a neoadjuvant, adjuvant or palliative treatment in various cancers. There is significant variation in clinical response to radiotherapy with or without traditional chemotherapy. Patients with a good response to radiotherapy demonstrate better clinical outcomes universally across different cancers. The PI3K/AKT/mTOR pathway upregulation has been linked to radiotherapy resistance. We reviewed the current literature exploring the role of inhibiting targets along this pathway, in enhancing radiotherapy response. We identified several studies using in vitro cancer cell lines, in vivo tumour xenografts and a few Phase I/II clinical trials. Most of the current evidence in this area comes from glioblastoma multiforme, non-small cell lung cancer, head and neck cancer, colorectal cancer, and prostate cancer. The biological basis for radiosensitivity following pathway inhibition was through inhibited DNA double strand break repair, inhibited cell proliferation, enhanced apoptosis and autophagy as well as tumour microenvironment changes. Dual PI3K/mTOR inhibition consistently demonstrated radiosensitisation of all types of cancer cells. Single pathway component inhibitors and other inhibitor combinations yielded variable outcomes especially within early clinical trials. There is ample evidence from preclinical studies to suggest that direct pharmacological inhibition of the PI3K/AKT/mTOR pathway components can radiosensitise different types of cancer cells. We recommend that future in vitro and in vivo research in this field should focus on dual PI3K/mTOR inhibitors. Early clinical trials are needed to assess the feasibility and efficacy of these dual inhibitors in combination with radiotherapy in brain, lung, head and neck, breast, prostate and rectal cancer patients.

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ObjectivesPartial or total resistance to preoperative chemoradiotherapy occurs in more than half of locally advanced rectal cancer patients. Several novel or repurposed drugs have been trialled to improve cancer cell sensitivity to radiotherapy, with limited success. We aimed to understand the mechanisms of resistance to chemoradiotherapy in rectal cancer using patient derived organoid models.DesignTo understand the mechanisms underlying this resistance, we compared the pre-treatment transcriptomes of patient-derived organoids (PDO) with measured radiotherapy sensitivity to identify biological pathways involved in radiation resistance coupled with single cell sequencing, genome wide CRISPR-Cas9 and targeted drug screens.ResultsRNA sequencing enrichment analysis revealed upregulation of PI3K/AKT/mTOR and epithelial mesenchymal transition pathway genes in radioresistant PDOs. Single-cell sequencing of pre & post-irradiation PDOs showed mTORC1 and PI3K/AKT upregulation, which was confirmed by a genome-wide CRSIPR-Cas9 knockout screen using irradiated colorectal cancer (CRC) cell lines. We then tested the efficiency of dual PI3K/mTOR inhibitors in improving cancer cell sensitivity to radiotherapy. After irradiation, significant AKT phosphorylation was detected (p=0.027) which was abrogated with dual PI3K/mTOR inhibitors and lead to significant radiosensitisation of the HCT116 cell line and radiation resistant PDO lines.ConclusionsThe PI3K/AKT/mTOR pathway upregulation contributes to radioresistance and its targeted pharmacological inhibition leads to significant radiosensitisation in CRC organoids, making it a potential target for clinical trials.

Background ObjectivesThe impact of tumor necrosis as a prognostic factor in gastrointestinal stromal tumor (GISTs) is still debated. The objective was to determine whether tumor necrosis is an independent risk factor for survival in patients with GISTs.MethodsPatients undergoing surgery for primary GIST from March 2003 to October 2018 at two sarcoma referral centers were retrospectively identified. Patients who received neoadjuvant imatinib were excluded. Multivariable Cox regression models were produced, to assess whether tumor necrosis was an independent predictor of either overall or recurrence‐free survival.ResultsForty‐one out of 195 (21.0%) patients had tumor necrosis. Tumor necrosis was associated with a significantly higher modified National Institute of Health risk score, with 29 out of 41 (70.7%) patients with necrosis classified as high risk, compared to 52 out of 153 (34.0%) without (p < .001). Tumor necrosis was found to be independently predictive of recurrence‐free survival (hazard ratio: 5.26, 95% CI: 2.62–10.56, p < .001) on multivariable analysis. At 5 years, 44.3% of patients with necrosis had either died or developed recurrence, compared to 9.9% of those without.ConclusionTumor necrosis is an independent predictor of recurrence‐free survival in patients with operable GISTs. It should be routinely reported by pathologists, and used by clinicians when counseling patients and deciding on adjuvant therapy.

BACKGROUNDBenign oesophageal strictures carry a significant level of morbidity, causing burdensome symptoms impacting on quality of life. Post-oesophagectomy anastomotic stricture rates as high as 41% have been reported in the literature. These can require endoscopic dilatation, often multiple times to relieve dysphagia. The aim of the present study was to determine a single surgeons stricture rate in a series of 2-stage Ivor-Lewis procedures, and to identify any independent risk factors in their development.AIMTo determine a single surgeons stricture rate in a series of 2-stage Ivor-Lewis procedures, and to identify any independent risk factors in their development.METHODSWe performed a retrospective analysis of a prospectively collected database of Ivor-Lewis oesophagectomy performed from 2004-2018 to determine the stricture rate. The database comprised a single-surgeon series of open, two-stage oesophagectomies with a circular stapled intra-thoracic anastomosis. Tumour location, histology, neoadjuvant chemotherapy, stapler size, T-stage and R-status were analysed to see if they could predict stricture formation. Stricture was defined as dysphagia requiring endoscopic dilatation. Patients with anastomotic leaks were excluded on the basis they would develop an anastomotic stricture.RESULTSOne hundred and seventy patients were collected in the database. Nineteen were excluded on the basis of anastomotic leak, perioperative death and early recurrence. One hundred and fifty-four patients (119 males, 35 females) with a mean age of 64 ± 10 years were eligible for analysis. A total of 15 patients developed strictures a median of 99 d (interquartile range: 84-133) after surgery, giving a Kaplan-Meier estimated stricture rate of 10% at one year. None of the factors considered were found to be significantly associated with strictures.CONCLUSIONIn this study the stricture rate was 10%, with the majority occurring in the first 100 d after surgery. No significant independent factors were found in the development of strictures.

Background The prognostic significance of histological organ involvement by retroperitoneal sarcoma subtype is unknown. The present study aimed to describe organ involvement across the subtypes, and the implications for survival. Methods Patients undergoing surgery for primary retroperitoneal sarcoma at the Queen Elizabeth Hospital, Birmingham from April 2005 to September 2018 were identified retrospectively. Histological organ involvement was classed as pushing, infiltrative or neither. Univariable and multivariable Cox regression models were produced to analyse the association between histological organ involvement and both overall (OS) and recurrence-free (RFS) survival for the cohort as a whole, and by histological subtype. Results Data were available for a total of 197 patients, of whom 171 (86.8 per cent) had at least one organ resected. Infiltrative organ behaviour was seen in 37 patients (18.8 per cent), and pushing behaviour in 67 (34.0 per cent). For the cohort as a whole, infiltration (hazard ratio (HR) 4.32, 95 per cent c.i. 2.35 to 7.93; P &lt; 0.001), but not pushing (HR 1.62, 0.90 to 2.92; P = 0.106), was associated with significantly shorter OS, in comparisons with a group with neither of these behaviours. However, this effect was found to differ significantly by histological subtype (P = 0.009). For patients with dedifferentiated liposarcoma, there was no significant association between tumour behaviour and either OS (P = 0.508) or RFS (P = 0.313). However, in leiomyosarcoma, infiltrative behaviour was associated with shorter OS (P = 0.002), and both infiltrative (P &lt; 0.001) and pushing (P = 0.010) behaviours were associated with shorter RFS, compared with tumours with neither behaviour. Multivariable analyses of both OS and RFS returned similar results. Conclusion The prognostic implications of organ involvement in retroperitoneal sarcoma vary by histological subtype.