•PET/CT is an important contributor towards sarcoma grading, prognostication and evaluation of treatment response.•PET/CT provides discriminative ability of tumour SUV to differentiate low- from ...high-grade sarcomas in suitable subtypes.•PET/CT facilitates early identification of patients who will respond to treatment.•PET/CT increases yield of staging by limiting its use to patients who are at greater risk metastases.•Larger prospective trials will be helpful to further establish the clinical value of PET/CT in sarcoma staging and restaging.
Sarcomas are a heterogeneous group of malignant tumours with variable clinical outcomes. Their presence in multiple body locations represents significant diagnostic and therapeutic challenges. Positron emission tomography/computed tomography (PET/CT) is an imaging tool that provides semiquantitative measurements of radiotracer concentration in tissue, such as SUVmax (standardised uptake value) and is increasingly used in clinical practice. This systematic review aims to evaluate the utility of PET/CT in sarcoma grading and prognostication, evaluation of treatment response, staging and restaging.
Relevant studies published from January 2003 to August 2017 evaluating the utility of PET/CT in sarcoma grading and prognostication, staging, evaluation of treatment response and restaging were systematically searched for in scientific databases (e.g. PubMed, Medline and Embase) using key terms, including “soft tissue sarcoma,” “osteosarcoma,” “utility” and “PET/CT”. Additionally, references of identified studies were reviewed. Study quality was assessed by “Quality Assessment of Diagnostic Accuracy Studies”.
A total of 12 prospective studies (level II to III evidence) were included in the review for tumour grading and prognostication. There was a strong correlation between SUV and tumour grade where majority of intermediate/ high-grade STS have a significantly higher SUVmax. PET/CT has also shown potential in prognostication where decrease in SUVmax correlated with recurrence-free survival in both osteosarcoma and STS. Furthermore, 8 prospective trials of level II to IV evidence according to Oxford Centre of Evidence-based Medicine (CEBM) demonstrated the use of PET/CT in early identification of patients who will respond to treatment where ≥60% decrease in FDG uptake resulted in sensitivity and specificity of 100% and 71% respectively for assessment of histopathologic response. 11 retrospective trials (level III to IV evidence) reported on the use of PET/CT in staging and restaging with heterogeneous results.
Overall, higher quality evidence demonstrated PET/CT to be an important contributor towards sarcoma grading, prognostication and evaluation of treatment response. Larger prospective trials will be helpful to further establish the clinical value of PET/CT in sarcoma staging and restaging.
Abstract
The controlled assembly of nanomaterials into desired architectures presents many opportunities; however, current preparations lack spatial precision and versatility in developing complex ...nano-architectures. Inspired by the amphiphilic nature of surfactants, we develop a facile approach to guide nanomaterial integration – spatial organization and distribution – in metal-organic frameworks (MOFs). Named surfactant tunable spatial architecture (STAR), the technology leverages the varied interactions of surfactants with nanoparticles and MOF constituents, respectively, to direct nanoparticle arrangement while molding the growing framework. By surfactant matching, the approach achieves not only tunable and precise integration of diverse nanomaterials in different MOF structures, but also fast and aqueous synthesis, in solution and on solid substrates. Employing the approach, we develop a dual-probe STAR that comprises peripheral working probes and central reference probes to achieve differential responsiveness to biomarkers. When applied for the direct profiling of clinical ascites, STAR reveals glycosylation signatures of extracellular vesicles and differentiates cancer patient prognosis.
Abstract
Ovarian cancer is associated with poor prognosis. Platinum resistance contributes significantly to the high rate of tumour recurrence. We aimed to identify a set of molecular markers for ...predicting platinum sensitivity. A signature predicting cisplatin sensitivity was generated using the Genomics of Drug Sensitivity in Cancer and The Cancer Genome Atlas databases. Four potential biomarkers (CYTH3, GALNT3, S100A14, and ERI1) were identified and optimized for immunohistochemistry (IHC). Validation was performed on a cohort of patients (n = 50) treated with surgical resection followed by adjuvant carboplatin. Predictive models were established to predict chemosensitivity. The four biomarkers were also assessed for their ability to prognosticate overall survival in three ovarian cancer microarray expression datasets from The Gene Expression Omnibus. The extreme gradient boosting (XGBoost) algorithm was selected for the final model to validate the accuracy in an independent validation dataset (n = 10).
CYTH3
and
S100A14
, followed by nodal stage, were the features with the greatest importance. The four gene signature had comparable prognostication as clinical information for two-year survival. Assessment of tumour biology by means of gene expression can serve as an adjunct for prediction of chemosensitivity and prognostication. Potentially, the assessment of molecular markers alongside clinical information offers a chance to further optimise therapeutic decision making.
Background & Aims The incidence of esophageal and junctional adenocarcinoma has increased 6-fold in the past 30 years and 5-year survival remains approximately 20%. Current staging is limited in its ...ability to predict survival which has ramifications for treatment choices. The aim of this study was to generate and validate a molecular prognostic signature for esophageal adenocarcinoma. Methods Gene expression profiling was performed and the resulting 42,000 gene signatures correlated with clinical and pathologic features for 75 snap-frozen esophageal and junctional resection specimens. External validation of selected targets was performed on 371 independent cases using immunohistochemistry to maximize clinical applicability. Results A total of 119 genes were associated significantly with survival and 270 genes with the number of involved lymph nodes. Filtering of these lists resulted in a shortlist of 10 genes taken forward to validation. Four genes proved to be prognostic at the protein level (deoxycytidine kinase DCK, 3′-phosphoadenosine 5′-phosphosulfate synthase 2 PAPSS2, sirtuin 2 SIRT2, and tripartite motif-containing 44 TRIM44) and were combined to create a molecular prognostic signature. This 4-gene signature was highly predictive of survival in the independent external validation cohort (0/4 genes dysregulated 5-year survival, 58%; 95% confidence interval CI, 36%–80%; 1–2/4 genes dysregulated 5-year survival, 26%; 95% CI, 20%–32%; and 3–4/4 genes dysregulated 5-year survival, 14%; 95% CI, 4%–24% ( P = .001). Furthermore, this 4-gene signature was independently prognostic in a multivariable model together with the existing clinical TNM staging system ( P = .013). Conclusions This study has generated a clinically applicable prognostic gene signature that independently predicts survival in an external validation cohort and may inform management decisions.
Extranodal natural killer/T-cell lymphoma (NKTL) is an aggressive type of non-Hodgkin lymphoma with dismal outcome. A better understanding of disease biology and key oncogenic process is necessary ...for the development of targeted therapy. Super-enhancers (SEs) have been shown to drive pivotal oncogenes in various malignancies. However, the landscape of SEs and SE-associated oncogenes remain elusive in NKTL.
We used Nano-ChIP-seq of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs NKTL primary tumor samples. Integrative analysis of RNA-seq and survival data further pinned down high value, novel SE oncogenes. We utilized shRNA knockdown, CRISPR-dCas9, luciferase reporter assay, ChIP-PCR to investigate the regulation of transcription factor (TF) on SE oncogenes. Multi-color immunofluorescence (mIF) staining was performed on an independent cohort of clinical samples. Various function experiments were performed to evaluate the effects of TOX2 on the malignancy of NKTL in vitro and in vivo.
SE landscape was substantially different in NKTL samples in comparison with normal tonsils. Several SEs at key transcriptional factor (TF) genes, including TOX2, TBX21(T-bet), EOMES, RUNX2, and ID2, were identified. We confirmed that TOX2 was aberrantly overexpressed in NKTL relative to normal NK cells and high expression of TOX2 was associated with worse survival. Modulation of TOX2 expression by shRNA, CRISPR-dCas9 interference of SE function impacted on cell proliferation, survival and colony formation ability of NKTL cells. Mechanistically, we found that RUNX3 regulates TOX2 transcription by binding to the active elements of its SE. Silencing TOX2 also impaired tumor formation of NKTL cells in vivo. Metastasis-associated phosphatase PRL-3 has been identified and validated as a key downstream effector of TOX2-mediated oncogenesis.
Our integrative SE profiling strategy revealed the landscape of SEs, novel targets and insights into molecular pathogenesis of NKTL. The RUNX3-TOX2-SE-TOX2-PRL-3 regulatory pathway may represent a hallmark of NKTL biology. Targeting TOX2 could be a valuable therapeutic intervene for NKTL patients and warrants further study in clinic.
Peritoneal sarcomatosis (PS) is a difficult entity to treat with limited options and guarded prognosis. We aimed to determine if the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) ...could offer superior local recurrence-free survival in patients with retroperitoneal sarcoma at high risk of developing PS as opposed to extended resection alone.
This is a single arm, phase II intervention study where all patients with recurrent localized retroperitoneal sarcoma considered at high risk of developing PS were considered for enrolment (ClinicalTrials.gov identifier: NCT03792867). Upon enrolment, patients underwent vigorous preoperative testing to ensure fitness for the procedure. During surgery, patients underwent extended resection and HIPEC with doxorubicin. Patients were followed-up every 2 weeks (± 10 days) for the first month and subsequently every three months (± 1 month) up to a year post-surgery, and were assessed for potential chemotherapy toxicity and post-treatment complications. After a year from resection and HIPEC, patients were followed-up either during routine clinic review or contacted via telephone every year (± 1 month) for 3 years.
Six patients were recruited but one patient dropped out due to adverse and unexpected intraoperative events. The remaining patients completed the procedure uneventfully. Post-HIPEC, all patients recurred with a disease-free interval ranging from six to 24 months. Three patients died due to complications from recurrent disease whereas the remaining three patients are alive as of their last visit. The overall survival at time at reporting ranged between 22 to 56 months.
The procedure is feasible with no major morbidity to patients. However, we are unable to recommend for it to be implemented as a routine procedure at this current stage due to lack of improved survival outcomes. Further multi-institutional studies may be conducted to yield better results.
Inflammatory myofibroblastic tumours (IMT) are spindle cell neoplasms most commonly seen in the lungs, with a wide variety of less common extrapulmonary sites including the mesentery, omentum, and ...intrabdominal sites. On cytological evaluation, these tumours can be difficult to diagnose, given the morphological mimics of other submucosal spindle cell neoplasms, which may be compounded by the relatively small amount of tissue and the uncommon nature of the diagnosis. Immunohistochemical staining and molecular studies for the ALK gene can prove useful for diagnosing this tumour. We present the cytological features of an IMT occurring in the rectum, the differential diagnoses, useful immunohistochemical staining patterns, and the additional finding of a novel ALK‐fusion in this entity.
The increasing prevalence of sampling of submucosal gastrointestinal lesions has led to a need for accurate diagnosis to guide treatment. Inflammatory myofibroblastic tumours (IMTs) are one such lesion that can be difficult to diagnose on cytology. This article reports a case of a rectal IMT diagnosed on cytology, discusses the pertinent differentials, and the presence of a novel fusion in this entity. It highlights the extent to which a single cytological specimen can be used for diagnostic evaluation and even molecular studies for confirmatory results.
Background: The performance of MRI versus CT in the detection and evaluation of peritoneal surface malignancies (PSM) remains unclear in the current literature. Our study is the first prospective ...study in an Asian center comparing the two imaging modalities, validated against intra-operative findings. Methods: A total of 36 patients with PSM eligible for CRS-HIPEC underwent both MRI and CT scans up to 6 weeks before the operation. The scans were assessed for the presence and distribution of PSM and scored using the peritoneal cancer index (PCI), which were compared against PCI determined at surgery. Results: Both MRI and CT were 100% sensitive and specific in detecting the overall presence of PSM. Across all peritoneal regions, the sensitivity and specificity for PSM detection was 49.1% and 93.0% for MRI, compared to 47.8% and 95.1% for CT (p = 0.76). MRI was more sensitive than CT for small bowel disease, although the difference did not reach statistical significance. Comparing PCI on imaging with intra-operative PCI, the mean difference was found to be −3.4 ± 5.4 (p < 0.01) for MRI, and −3.9 ± 4.1 (p < 0.01) for CT. The correlation between imaging and intra-operative PCI was poor, with a concordance coefficient of 0.76 and 0.79 for MRI and CT, respectively. Within individual peritoneal regions, there was also poor agreement between imaging and intra-operative PCI for both modalities, other than in regions 1 and 3. Conclusion: MRI and CT are comparable in the detection and evaluation of PSM. While sensitive in the overall detection of PSM, they are likely to underestimate the true disease burden.
Peritoneal carcinomatosis (PC) is often associated with malnutrition and an inability to tolerate enteral feeding. Although total parenteral nutrition (TPN) can be lifesaving for patients with no ...other means of nutritional support, its use in the management of PC patients remains controversial. Therefore, a systematic review and meta-analysis was performed to evaluate the benefit of TPN on the overall survival of PC patients, in accordance with PRISMA guidelines. A total of 187 articles were screened; 10 were included in this review and eight were included in the meta-analysis. The pooled median overall survival of patients who received TPN was significantly higher than patients who did not receive TPN (p = 0.040). When only high-quality studies were included, a significant survival advantage was observed in PC patients receiving TPN (p < 0.001). Subgroup analysis of patients receiving chemotherapy demonstrated a significant survival benefit (p = 0.008) associated with the use of TPN. In conclusion, TPN may improve survival outcomes in PC patients. However, further studies are needed to conclude more definitively on the effect of TPN.
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