Risk Factors for the Development of Early Recurrence in Patients with Primary Retroperitoneal Sarcoma.

BACKGROUND: Disease recurrence after retroperitoneal sarcoma (RPS) surgery is common, and resection may offer no benefit for patients who experience recurrence early. This study examined the incidence of early recurrence (EREC) in RPS patients, and the association between EREC and prognosis, aiming to identify the factors associated with EREC. METHODS: Patients undergoing surgery for primary RPS from 2008 to 2019 at two tertiary RPS centers were analyzed. The study defined EREC as any evidence of local recurrence and/or distant metastases on the CT scan up to 6 months after surgery. Overall survival (OS) was calculated using the Kaplan-Meier method. A multivariable analysis was performed to identify independent predictors of EREC. RESULTS: Of the 692 patients who underwent surgery during the study period, 657 were included in the analysis. Sixty-five of these patients (9.9%; 95% confidence interval [CI], 7.7-12.4%) developed EREC. Five-year OS was 3% for the patients with EREC versus 76% for those without EREC (p < 0.001). Patient characteristics were compared between the EREC and non-EREC patients, and EREC was found to be significantly associated with Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.006), tumor histology (p = 0.002), tumor grading (p < 0.001), radiotherapy (p = 0.04), and postoperative complications measured as a comprehensive complications index value (p = 0.003). However, the only significant independent predictor of EREC in the multivariable analysis was grade 3 tumors, with an odds ratio of 14.8 (95% CI, 4.44-49.2; p < 0.001). CONCLUSION: Early recurrence is associated with a poor prognosis, and a high tumor grade is an independent predictor for the development of EREC. Patients with EREC may benefit the most from new therapeutic options such as neoadjuvant chemotherapy.

Association Between Ageing and Short-Term Survival Outcomes in Patients Undergoing Surgery for Primary Retroperitoneal Sarcoma.

BACKGROUND: As the population ages, more elderly patients are receiving surgery for retroperitoneal sarcoma (RPS). However, high-quality data investigating associations between ageing and prognosis are lacking. Our study aimed to investigate whether ageing is associated with inferior short-term survival outcomes after RPS surgery. PATIENTS AND METHODS: Patients undergoing surgery for primary RPS between 2008 and 2019 at two tertiary sarcoma centres were analysed. The primary outcome was 1-year mortality, and the primary explanatory variable was patient age, classified as: < 55, 55-64, 65-74 or 75+ years. RESULTS: The 692 patients undergoing surgery (mean age 60.8 ± 13.8 years) had a 1-year mortality rate of 9.4%, which differed significantly by age (p < 0.001), with rates of 7.2%, 6.9%, 8.7% and 22.8% for the < 55, 55-64, 65-74 and 75+ years groups, respectively. The distribution of causes of death also differed significantly by age (p = 0.023), with 22% and 28% of deaths in the 65-74 and 75+ years groups caused by post-operative complications, versus none in the < 55 and 55-64 years groups. On multivariable analysis, age of 75+ years (versus < 55 years) was a significant independent predictor of 1-year mortality [odds ratio (OR) 7.05, 95% confidence interval (CI) 2.63-18.9, p < 0.001]; no significant increase in risk was observed in the 55-64 (OR 0.72, 95% CI 0.28-1.87) or 65-74 (OR 0.89, 95% CI 0.37-2.15) years groups. CONCLUSIONS: Post-operative complications are an important cause of deaths in elderly patients. These findings are relevant to decision-making and counselling when surgery is considered for patients with RPS.

Cumulative Burden of Postoperative Complications in Patients Undergoing Surgery for Primary Retroperitoneal Sarcoma.

BACKGROUND: Correlations between postoperative complications and oncological outcomes have been reported in several malignancies, but their impact in retroperitoneal sarcoma (RPS) is unclear. Our study aimed to evaluate the association between postoperative complications and prognosis in patients with RPS. METHODS: Patients undergoing surgery for primary RPS from 2008 to 2019 at a sarcoma center were evaluated. The cumulative burden of postoperative complications was quantified using the Comprehensive Complication Index (CCI), and associations with local recurrence (LR), distant metastases (DM) and overall survival (OS) were assessed. RESULTS: Data were available for 191 patients, of whom 160 (82.9%) developed at least one postoperative complication, with a median CCI of 20.9 (interquartile range 8.7-33.5). After postoperative deaths were excluded (n = 3, 1.6%), the remaining patients were divided into those with a CCI of 0-20.9 (n = 97) and > 20.9 (n = 91). Patients with a CCI >20.9 had significantly shorter OS than those with a CCI of 0-20.9 (43.3% vs. 69.5% at 5 years; p = 0.005), and this difference remained significant after multivariable adjustment for patient- and treatment-related factors [hazard ratio (HR) 2.31, 95% confidence interval (CI) 1.30-4.09; p = 0.004]. However, CCI > 20.9 was not found to be a significant independent predictor of either LR (HR 1.30, 95% CI 0.76-2.23; p = 0.333) or DM (HR 1.08, 95% CI 0.61-1.93; p = 0.786). CONCLUSION: Increasing complication burden, as quantified by the CCI, is a significant independent predictor of OS; however, there is no evidence of a significant association with either LR or DM, which may be more related to tumor biological factors.

Liver resection for sarcoma metastases: A systematic review and experience from two European centres.

INTRODUCTION: Studies reporting outcomes of liver resection for sarcoma metastases (LRSM) typically include gastrointestinal stromal tumours (GIST), or pooled analyses of "non-colorectal liver metastases", which do not reflect the subgroup of patients with sarcomatous liver metastases. This study aimed to perform a systematic review to evaluate oncological and surgical outcomes in patients undergoing LRSM, and to report new data from two tertiary institutions. METHODS: MEDLINE and the Cochrane Library were searched for studies reporting oncological and surgical outcomes after LRSM, following PRISMA guidelines. Studies reporting liver resection for GIST were excluded. The resulting studies were pooled, with data from two European centres. RESULTS: Six studies of LSRM were included, comprising 212 patients from previously reported series and 24 patients from ours, with median follow-up times of 18-53 months. Postoperative mortality rates ranged from 0 to 9%, and the pooled overall survival (OS) was 89% (95% CI: 83-96%), and 31% (95% CI: 14-47%) at one and five years, respectively (median: 36 months). The presence of synchronous extra-hepatic metastases was found to be a significant risk factor for shorter OS in two cohorts, with hazard ratios of 3.7 (p < 0.001) and 9.1 (p = 0.016), respectively. The largest reported series also found larger metastases (≥100 mm), lack of response to chemotherapy and a shorter disease-free interval to be associated with significantly shorter OS after LSRM. CONCLUSIONS: Patients undergoing LRSM with negative prognostic factors such as the presence of extra-hepatic metastases are unlikely to benefit from surgery. Acceptable medium- and long-term survival may be achievable in highly selected patients.

Improved Biopsy Accuracy in Retroperitoneal Dedifferentiated Liposarcoma.

BACKGROUND: Biopsy sensitivity in retroperitoneal dedifferentiated liposarcoma (DDLPS) is variable. Patients with grade 3 DDLPS face a significant risk of metastatic disease and may potentially benefit from neoadjuvant therapy, making highly accurate pretherapy diagnosis essential. Our study aimed to establish whether diagnostic sensitivity could be improved by targeting solid areas of tumor on percutaneous biopsy. METHODS: Between 2016 and 2019, data on patients with suspected primary retroperitoneal sarcoma who underwent a biopsy were collected, and diagnostic accuracy was calculated. These data were compared with our previously reported series from 2005 to 2016. For DDLPS tumors, comparisons were then made between biopsies that targeted the solid component and those that did not. RESULTS: Data were available for 121 patients in the current series and 238 from the previous study. The proportion of biopsies returning a histological subtype concordant with postoperative pathology was 83% in the current series, marking a significant improvement over our previous study (67%, p = 0.001). For diagnosis of DDLPS, biopsy sensitivity improved from 40 to 74% (p < 0.001), with an increase from 13 to 50% (p = 0.006) where grade 3 DDLPS was treated as a separate disease. Within the current series, targeted biopsy yielded a sensitivity of 100% for identifying DDLPS, compared with 10% in nontargeted biopsy (p < 0.001). CONCLUSION: Systematic targeting of solid areas of tumor within suspected retroperitoneal liposarcoma has improved sensitivity for detection of both DDLPS and grade 3 DDLPS on biopsy. This approach minimizes the risk of underdiagnosis of patients with DDLPS who could benefit from neoadjuvant chemotherapy.

Neoadjuvant and adjuvant strategies in retroperitoneal sarcoma.

Extended surgery remains the mainstay of treatment in retroperitoneal sarcoma, although conflicting data exist on the benefit of neoadjuvant and adjuvant therapies, particularly with regard to tumour grade and histological type. Experience of radiotherapy and chemotherapy in extremity soft tissue sarcoma can inform treatment strategies, however these data cannot be universally extrapolated to the retroperitoneum where disease biology and anatomical considerations are different. The present review sets a historical context before discussing recent evidence and on-going multi-centre trials in retroperitoneal sarcoma. Promising data on histologically- and molecularly-targeted chemotherapy are discussed and the need for centralisation of retroperitoneal sarcoma services in order to facilitate large international collaborative trials is emphasised.

Automated cytological detection of Barrett's neoplasia with infrared spectroscopy.

BACKGROUND: Development of a nonendoscopic test for Barrett's esophagus would revolutionize population screening and surveillance for patients with Barrett's esophagus. Swallowed cell collection devices have recently been developed to obtain cytology brushings from the esophagus: automated detection of neoplasia in such samples would enable large-scale screening and surveillance. METHODS: Fourier transform infrared (FTIR) spectroscopy was used to develop an automated tool for detection of Barrett's esophagus and Barrett's neoplasia in esophageal cell samples. Cytology brushings were collected at endoscopy, cytospun onto slides and FTIR images were measured. An automated cell recognition program was developed to identify individual cells on the slide. RESULTS: Cytology review and contemporaneous histology was used to inform a training dataset containing 141 cells from 17 patients. A classification model was constructed by principal component analysis fed linear discriminant analysis, then tested by leave-one-sample-out cross validation. With application of this training model to whole slide samples, a threshold voting system was used to classify samples according to their constituent cells. Across the entire dataset of 115 FTIR maps from 66 patients, whole samples were classified with sensitivity and specificity respectively as follows: normal squamous cells 79.0% and 81.1%, nondysplastic Barrett's esophagus cells 31.3% and 100%, and neoplastic Barrett's esophagus cells 83.3% and 62.7%. CONCLUSIONS: Analysis of esophageal cell samples can be performed with FTIR spectroscopy with reasonable sensitivity for Barrett's neoplasia, but with poor specificity with the current technique.

Biphasic malignant tumours of the abdominal cavity.

Carcinosarcomas (CS) are uncommon, highly aggressive, biphasic tumours consisting of both sarcomatous and carcinomatous elements. They appear to originate from a common cell of origin, either via transformation from a single premature precursor or conversion of a mature epithelial cell through an epithelial-mesenchymal transition. CS should be considered a unique cancer subtype with cells typically displaying diffuse mitotic activity and widespread atypical mitoses predisposing to early metastasis and a tendency to local recurrence following resection. This review addresses the pathophysiology of CS and discusses its presentation, natural history and management at a variety of sites within the abdominal cavity and retroperitoneum.

Myeloid Sarcoma: Presentation, Diagnosis, and Treatment.

Myeloid sarcoma is an extramedullary tumor of immature granulocytic cells. It is a rare condition, most often associated with acute myeloid leukemia (AML), although in some rare cases it may present in nonleukemic patients. It should therefore be considered as a differential diagnosis of any atypical cellular infiltrate. It may occur at any site, leading to very varied clinical presentations. Diagnosis is challenging and relies on a high index of suspicion as well as radiology, histology, immunophenotyping, and molecular analyses, which also are essential for risk stratification and treatment planning. Systemic chemotherapy using AML-like regimens should be commenced early, even in nonleukemic disease. Surgery and/or radiotherapy may be indicated for symptomatic lesions or tumors causing local organ dysfunction or obstruction. Allogeneic hematopoietic stem cell transplantation has demonstrated promising results, particularly in patients who achieved complete remission with AML-induction protocols, and recent advances in genetic profiling may enable the development of novel targeted therapies. Prospective multicenter controlled trials are required to further refine management decisions and investigate the role of novel targeted therapies.

Has integrated 18F FDG PET/CT improved staging, reduced early recurrence or increased survival in oesophageal cancer?

BACKGROUND: Survival in oesophageal cancer remains poor with high post-operative recurrence rates. PET/CT was introduced to the Three-Counties Cancer Network (3CCN) in 2006 to detect 'occult' metastatic disease not seen with conventional staging modalities. This study aims to determine whether the introduction of Integrated fluorodeoxyglucose (18F) Positron Emission Tomography (PET/CT) has changed the management, improved survival or reduced the rate of early post-operative recurrence in patients with operable oesophageal cancer. METHODS: A retrospective review was undertaken of all patients diagnosed with oesophageal cancer in the 3CCN from 2005 to 2009. Early recurrence was defined as proven recurrence locally or at a distant site within one year of resection. RESULTS: 725 patients were identified. 200 (27.6%) patients underwent staging PET/CT. PET/CT altered treatment intent in 19 (9.5%) patients. 128 (17.7%) patients underwent oesophageal resection, 90 (70.3%) of which had a staging PET/CT. No significant difference was noted in post-operative mortality (4.4% Vs 5.3%, p = 0.8) or early recurrence where PET/CT was performed when adjusted for age, sex, stage or neo-adjuvant chemotherapy (p = 0.761, OR 1.136[95% CI 0.499-2.585]). PET/CT had no significant effect on survival (log-rank test; Chi-square 0.710, p = 0.4). CONCLUSION: PET/CT has improved the accuracy of oesophageal cancer staging avoiding potentially unnecessary surgery. Ultimately however, its use has had no effect on early recurrence or survival rates. Inaccurate identification of occult metastatic disease prior to the introduction of staging PET/CT does not appear to be the primary cause of early recurrence in patients with oesophageal cancer.

Strategies for the prevention of oesophageal adenocarcinoma.

The incidence of oesophageal adenocarcinoma has increased by 500% over the past 30 years [1]. Improved understanding of the mechanisms of neoplastic progression provides an opportunity to reverse this trend. A thorough review of emerging strategies aiming to prevent the formation of oesophageal malignancy is presented. These include dietary modification, chemoprevention, early endoscopic identification and treatment of premalignant disease, and the potential for a non-endoscopic screening test. Oesophageal adenocarcinoma has become a major public health problem in the West and it is essential that clinicians are fully informed of risk reduction strategies so that they can be actively promoted in the community.

Utilising non-consensus pathology measurements to improve the diagnosis of oesophageal cancer using a Raman spectroscopic probe.

The application of semi-supervised methodology to improve the classification performance of a Raman spectroscopic probe for the diagnosis of oesophageal cancer is described. It is well known that gold standard histopathology diagnosis can be highly subjective, particularly for diseases which have several stages, such as cancer. A 'consensus' pathology decision can be obtained to ensure a robust gold standard by obtaining a diagnosis from several experts and samples are then only included in standard classification models if they have been assigned the same pathology by all experts. This can result in a significant number of samples that are excluded from the analysis as no consensus was reached. In this work semi-supervised methodology was used to extend Principal Component Analysis followed by Linear Discriminant Analysis (PCA-LDA) to incorporate samples without consensus pathology when discriminating between benign and oesophageal cancer specimens measured using a Raman endoscopic probe ex vivo. We demonstrate that a fully semi-supervised approach improved sensitivity and specificity from 73% and 78% (PCA-LDA) to 78% and 84% (semi-supervised) for discriminating between intestinal metaplasia and dysplasia and from 44% and 66% (PCA-LDA) to 63% and 72% (semi-supervised) when discriminating between intestinal metaplasia and low grade dysplasia.

Endoscopic Raman spectroscopy enables objective diagnosis of dysplasia in Barrett's esophagus.

BACKGROUND: Early detection and targeted endoscopic resection of Barrett's esophagus-associated high-grade dysplasia (HGD) can prevent progression to invasive esophageal malignancy. Raman spectroscopy, a highly sophisticated analytical technique, has been translated into an endoscopic tool to facilitate rapid, objective diagnosis of dysplasia in the esophagus. OBJECTIVE: To evaluate the ability of endoscopic Raman spectroscopy (ERS) to objectively detect esophageal HGD and adenocarcinoma. DESIGN: A total of 798 one-second spectra were measured from 673 ex vivo esophageal tissue samples, collected from patients with Barrett's esophagus by using a novel endoscopic Raman probe. Spectra were correlated with consensus histopathology. Multivariate analysis was used to evaluate the classification accuracy of ERS ex vivo. SETTING: Probe measurements were conducted in the laboratory. Tissue specimens were collected from the operating theatre and endoscopy unit. PATIENTS: Tissue from 62 patients was included in the study. INTERVENTIONS: Endoscopic biopsy/resection or esophagectomy was performed where indicated clinically. MAIN OUTCOME MEASUREMENT: Diagnostic performance of ERS for detection of HGD and esophageal adenocarcinoma. RESULTS: ERS demonstrated a sensitivity of 86% and a specificity of 88% for detecting HGD and adenocarcinoma. The ability to grade dysplasia and differentiate intestinal metaplasia from nonintestinal metaplasia columnar-lined esophagus was also demonstrated. Diagnostic classification was based on objective measurement of the biochemical profile of different tissue types. The potential for combination ERS and narrow-band imaging was also demonstrated. LIMITATIONS: Measurements were taken from ex vivo tissue. CONCLUSION: ERS enables rapid, accurate, objective diagnosis of superficial esophageal disease (metaplasia, dysplasia, intramucosal cancer) in clinically applicable time scales.

Advances in the clinical application of Raman spectroscopy for cancer diagnostics.

Light interacts with tissue in a number of ways including, elastic and inelastic scattering, reflection and absorption, leading to fluorescence and phosphorescence. These interactions can be used to measure abnormal changes in tissue. Initial optical biopsy systems have potential to be used as an adjunct to current investigative techniques to improve the targeting of blind biopsy. Future prospects with molecular-specific techniques may enable objective optical detection providing a real-time, highly sensitive and specific measurement of the histological state of the tissue. Raman spectroscopy has the potential to identify markers associated with malignant change and could be used as diagnostic tool for the early detection of precancerous and cancerous lesions in vivo. The clinical requirements for an objective, non-invasive, real-time probe for the accurate and repeatable measurement of pathological state of the tissue are overwhelming. This paper discusses some of the recent advances in the field.

Assessment of a custom-built Raman spectroscopic probe for diagnosis of early oesophageal neoplasia.

We evaluate the potential of a custom-built fiber-optic Raman probe, suitable for in vivo use, to differentiate between benign, metaplastic (Barrett's oesophagus), and neoplastic (dysplastic and malignant) oesophageal tissue ex vivo on short timescales. We measured 337 Raman spectra (λ(ex)=830 nm; P(ex)=60 mW; t=1 s) using a confocal probe from fresh (298) and snap-frozen (39) oesophageal tissue collected during surgery or endoscopy from 28 patients. Spectra were correlated with histopathology and used to construct a multivariate classification model which was tested using leave one tissue site out cross-validation in order to evaluate the diagnostic accuracy of the probe system. The Raman probe system was able to differentiate, when tested with leave one site out cross-validation, between normal squamous oesophagus, Barrett's oesophagus and neoplasia with sensitivities of (838% to 6%) and specificities of (89% to 99%). Analysis of a two group model to differentiate Barrett's oesophagus and neoplasia demonstrated a sensitivity of 88% and a specificity of 87% for classification of neoplastic disease. This fiber-optic Raman system can provide rapid, objective, and accurate diagnosis of oesophageal pathology ex vivo. The confocal design of this probe enables superficial mucosal abnormalities (metaplasia and dysplasia) to be classified in clinically applicable timescales paving the way for an in vivo trial.

Advanced endoscopic imaging in Barrett's oesophagus.

Barrett's oesophagus is a metaplastic condition with an inherent risk of progression to adenocarcinoma. It is essential to identify dysplastic changes within Barrett's oesophagus in order to individualise surveillance strategies and establish which patients warrant endoscopic treatment. There is a trend towards endoscopic resection of focal high-grade dysplasia followed by whole segment ablation. However, endoscopic identification of dysplastic lesions is unreliable and subjective making targeted therapy extremely difficult. In addition, the current practice of taking random quadrantic biopsies may miss dysplastic disease and intramucosal adenocarcinoma. Several advanced endoscopic imaging techniques have been described and tested in clinical trials in an effort to improve the detection of early lesions, although none are routinely used in clinical practice. In this article we will review these techniques and discuss their potential for clinical implementation. We will also discuss the potential benefits of multimodal imaging and highlight several newer techniques which have shown early promise for in vivo diagnosis.

Raman spectroscopy: a potential tool for early objective diagnosis of neoplasia in the oesophagus.

There is a profound clinical need for a diagnostic tool that will enable clinicians to identify early neoplastic change in the oesophagus. Raman Spectroscopy (RS) has demonstrated the potential to provide non-invasive, rapid, objective diagnosis of endoscopically invisible precancerous oesophageal dysplasia in vitro. RS analyses biological material to identify highly specific biochemical information that can be used to influence clinical care. Raman spectroscopic mapping could provide automated assessment of tissue biopsies to aid histopathological diagnosis in vitro. Furthermore, the recent development of fibre-optic Raman probes has enabled endoscopic assessment of oesophageal mucosa in vivo. Accurate identification of dysplasia will enable targeted endoscopic resection of early lesions preventing the development of oesophageal cancer. This review summarises the development of Raman systems for use as laboratory based analytical adjuncts and endoscopic diagnostic tools in the distal oesophagus.