A Systematic Review and Meta-Analysis of Mapping Biopsy for Primary Extramammary Paget's Disease in Reducing Recurrence Following Surgical Excision.

Objective: To examine the association between the performance of mapping biopsies and surgical outcomes postexcision of extramammary Paget's disease (EMPD). Background: Primary EMPD is a rare entity associated with poorly defined surgical margins and difficult-to-access sites of lesions. Surgical resection with clear margins remains the preferred management method. The use of mapping biopsies might be beneficial, particularly in lowering disease recurrence. Methods: Available literature was reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology before a fixed-effect meta-analysis was performed to identify the presence of a correlation between performing mapping biopsies and positive margins on permanent sections as well as disease-free survival. Additional study results not included in the quantitative assessment were qualitatively assessed and reported. Results: A total of 12 studies were shortlisted for final analysis. 294 patients who underwent mapping biopsies and 48 patients who did not undergo mapping biopsies were included in the assessment. Forest plot analysis revealed a pooled rate ratio of 0.50 (95% CI, 0.32-0.77) in the prevalence of positive margins in patients with mapping biopsies performed as compared to patients without. The pooled rate ratio of the prevalence of disease-free survival in patients with mapping biopsies performed as compared to patients without was 1.38 (95% CI, 1.03-1.84). Qualitative assessment of the remaining selected studies revealed equivocal results. Conclusions: Mapping biopsies are able to improve EMPD surgical excision outcomes but given the rarity of the disease and heterogeneity of mapping biopsy procedures, further confirmation with randomized controlled trials or a larger patient pool is necessary.

Inferring cancer disease response from radiology reports using large language models with data augmentation and prompting.

OBJECTIVE: To assess large language models on their ability to accurately infer cancer disease response from free-text radiology reports. MATERIALS AND METHODS: We assembled 10 602 computed tomography reports from cancer patients seen at a single institution. All reports were classified into: no evidence of disease, partial response, stable disease, or progressive disease. We applied transformer models, a bidirectional long short-term memory model, a convolutional neural network model, and conventional machine learning methods to this task. Data augmentation using sentence permutation with consistency loss as well as prompt-based fine-tuning were used on the best-performing models. Models were validated on a hold-out test set and an external validation set based on Response Evaluation Criteria in Solid Tumors (RECIST) classifications. RESULTS: The best-performing model was the GatorTron transformer which achieved an accuracy of 0.8916 on the test set and 0.8919 on the RECIST validation set. Data augmentation further improved the accuracy to 0.8976. Prompt-based fine-tuning did not further improve accuracy but was able to reduce the number of training reports to 500 while still achieving good performance. DISCUSSION: These models could be used by researchers to derive progression-free survival in large datasets. It may also serve as a decision support tool by providing clinicians an automated second opinion of disease response. CONCLUSIONS: Large clinical language models demonstrate potential to infer cancer disease response from radiology reports at scale. Data augmentation techniques are useful to further improve performance. Prompt-based fine-tuning can significantly reduce the size of the training dataset.

Prospective Comparison of the Performance of MRI Versus CT in the Detection and Evaluation of Peritoneal Surface Malignancies.

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.

Radioembolisation with Y90-resin microspheres followed by nivolumab for advanced hepatocellular carcinoma (CA 209-678): a single arm, single centre, phase 2 trial.

BACKGROUND: Therapeutic synergism between radiotherapy and immune checkpoint blockade has been observed in preclinical models of hepatocellular carcinoma. We aimed to study the safety and efficacy of sequential radioembolisation with yttrium-90-resin microspheres (Y90-radioembolisation) followed by nivolumab in patients with advanced hepatocellular carcinoma. METHODS: Patients with Child-Pugh A cirrhosis and advanced hepatocellular carcinoma not suitable for curative surgery were treated with Y90-radioembolisation followed by intravenous nivolumab 240 mg 21 days after Y90-radioembolisation and every 2 weeks thereafter. The primary endpoint, assessed in the per-protocol population, was the objective response rate, determined by RECIST version 1.1, defined as the proportion of patients with a confirmed complete or partial response observed for lesions both within and outside the Y90-radioembolisation field. This study is registered with ClinicalTrials.gov, NCT03033446 and has been completed. FINDINGS: 40 patients were enrolled, of whom 36 received Y90-radioembolisation followed by nivolumab. One (3%) patient had a complete response and ten (28%) had a partial response; the objective response rate was 30·6% (95% CI 16·4-48·1). The most common treatment-related adverse events of any grade were pruritus (18 [50%] of 36 patients) and maculopapular rash (13 [36%]). Two (6%) patients experienced grade 3-4 treatment-related adverse events: one patient had a grade 3 increase in alanine aminotransferase levels, grade 3 bilirubin increase, and grade 4 increase in aspartate aminotransferase levels, while the other had a grade 3 maculopapular rash. Five (14%) patients had a treatment-related serious adverse event (Steven-Johnson syndrome, hepatitis E infection, fever, liver abscesses, and ascites). INTERPRETATION: Y90-radioembolisation followed by nivolumab resulted in an encouraging objective response rate in patients with advanced hepatocellular carcinoma, although the activity observed was not as high as the study was powered for. This strategy should be further evaluated in patients with Barcelona Clinic Liver Clinic (BCLC) stage B hepatocellular carcinoma that is ineligible or refractory to transarterial chemoembolisation and patients with BCLC C disease without extrahepatic spread. FUNDING: National Medical Research Council Singapore, Bristol-Myers Squibb, Sirtex.

Real-World Data on Clinical Outcomes of Patients with Liver Cancer: A Prospective Validation of the National Cancer Centre Singapore Consensus Guidelines for the Management of Hepatocellular Carcinoma.

INTRODUCTION: Real-world management of patients with hepatocellular carcinoma (HCC) is crucially challenging in the current rapidly evolving clinical environment which includes the need for respecting patient preferences and autonomy. In this context, regional/national treatment guidelines nuanced to local demographics have increasing importance in guiding disease management. We report here real-world data on clinical outcomes in HCC from a validation of the Consensus Guidelines for HCC at the National Cancer Centre Singapore (NCCS). METHOD: We evaluated the NCCS guidelines using prospectively collected real-world data, comparing the efficacy of treatment received using overall survival (OS) and progression-free survival (PFS). Treatment outcomes were also independently evaluated against 2 external sets of guidelines, the Barcelona Clinic Liver Cancer (BCLC) and Hong Kong Liver Cancer (HKLC). RESULTS: Overall treatment compliance to the NCCS guidelines was 79.2%. Superior median OS was observed in patients receiving treatment compliant with NCCS guidelines for early (nonestimable vs. 23.5 months p < 0.0001), locally advanced (28.1 vs. 22.2 months p = 0.0216) and locally advanced with macrovascular invasion (10.3 vs. 3.3 months p = 0.0013) but not for metastatic HCC (8.1 vs. 6.8 months p = 0.6300), but PFS was similar. Better clinical outcomes were seen in BCLC C patients who received treatment compliant with NCCS guidelines than in patients with treatment only allowed by BCLC guidelines (median OS 14.2 vs. 7.4 months p = 0.0002; median PFS 6.1 vs. 4.0 months p = 0.0286). Clinical outcomes were, however, similar for patients across all HKLC stages receiving NCCS-recommended treatment regardless of whether their treatment was allowed by HKLC. CONCLUSION: The high overall compliance rate and satisfactory clinical outcomes of patients managed according to the NCCS guidelines confirm its validity. This validation using real-world data considers patient and treating clinician preferences, thus providing a realistic analysis of the usefulness of the NCCS guidelines when applied in the clinics.

Development of a microRNA Panel for Classification of Abnormal Mammograms for Breast Cancer.

Mammography is extensively used for breast cancer screening but has high false-positive rates. Here, prospectively collected blood samples were used to identify circulating microRNA (miRNA) biomarkers to discriminate between malignant and benign breast lesions among women with abnormal mammograms. The Discovery cohort comprised 72 patients with breast cancer and 197 patients with benign breast lesions, while the Validation cohort had 73 and 196 cancer and benign cases, respectively. Absolute expression levels of 324 miRNAs were determined using RT-qPCR. miRNA biomarker panels were identified by: (1) determining differential expression between malignant and benign breast lesions, (2) focusing on top differentially expressed miRNAs, and (3) building panels from an unbiased search among all expressed miRNAs. Two-fold cross-validation incorporating a feature selection algorithm and logistic regression was performed. A six-miRNA biomarker panel identified by the third strategy, had an area under the curve (AUC) of 0.785 and 0.774 in the Discovery and Validation cohorts, respectively, and an AUC of 0.881 when differentiating between cases versus those with benign lesions or healthy individuals with normal mammograms. Biomarker panel scores increased with tumor size, stage and number of lymph nodes involved. Our work demonstrates that circulating miRNA signatures can potentially be used with mammography to differentiate between patients with malignant and benign breast lesions.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging as Imaging Biomarker for Vascular Normalization Effect of Infigratinib in High-FGFR-Expressing Hepatocellular Carcinoma Xenografts.

PURPOSE: Overexpression of fibroblast growth factor receptor (FGFR) contributes to tumorigenesis, metastasis, and poor prognosis of hepatocellular carcinoma (HCC). Infigratinib-a pan-FGFR inhibitor-potently suppresses the growth of high-FGFR-expressing HCCs in part via alteration of the tumor microenvironment and vessel normalization. In this study, we aim to assess the utility of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) as a non-invasive imaging technique to detect microenvironment changes associated with infigratinib and sorafenib treatment in high-FGFR-expressing HCC xenografts. PROCEDURES: Serial DCE-MRIs were performed on 12 nude mice bearing high-FGFR-expressing patient-derived HCC xenografts to quantify tumor microenvironment pre- (day 0) and post-treatment (days 3, 6, 9, and 15) of vehicle, sorafenib, and infigratinib. DCE-MRI data were analyzed using extended generalized kinetic model and two-compartment distributed parameter model. After treatment, immunohistochemistry stains were performed on the harvested tumors to confirm DCE-MRI findings. RESULTS: By treatment day 15, infigratinib induced tumor regression (70 % volume reduction from baseline) while sorafenib induced relative growth arrest (185 % volume increase from baseline versus 694 % volume increase from baseline of control). DCE-MRI analysis revealed different changes in microcirculatory parameters upon exposure to sorafenib versus infigratinib. While sorafenib induced microenvironment changes similar to those of rapidly growing tumors, such as a decrease in blood flow (F), fractional intravascular volume (vp), and permeability surface area product (PS), infigratinib induced the exact opposite changes as early as day 3 after treatment: increase in F, vp, and PS. CONCLUSIONS: Our study demonstrated that DCE-MRI is a reliable non-invasive imaging technique to monitor tumor microcirculatory response to FGFR inhibition and VEGF inhibition in high-FGFR-expressing HCC xenografts. Furthermore, the microcirculatory changes from FGFR inhibition manifested early upon treatment initiation and were reliably detected by DCE-MRI, creating possibilities of combinatorial therapy for synergistic effect.

Changing trends in the clinicopathological features, practices and outcomes in the surgical management for cystic lesions of the pancreas and impact of the international guidelines: Single institution experience with 462 cases between 1995-2018.

INTRODUCTION: The impact on clinical practice of the international guidelines including the Sendai Guidelines (SG06) and Fukuoka Guidelines (FG12) on the management of cystic lesions of the pancreas (CLP) has not been well-studied. The primary aim was to examine the changing trends and outcomes in the surgical management of CLP in our institution over time and to determine the impact of these guidelines on our institution practice. METHODS: 462 patients with surgically-treated CLP were retrospectively reviewed and classified under the 2 guidelines. The cohort was divided into 3 time periods: 1998-2006, 2007-2012 and 2013 to 2018. RESULTS: Comparison across the 3 time periods demonstrated significantly increasing frequency of older patients, asymptomatic CLP, male gender, smaller tumor size, elevated Ca 19-9, use of magnetic resonance imaging (MRI) and use of endoscopic ultrasound (EUS) prior to surgery. There was also significantly increasing frequency of adherence to the international guidelines as evidenced by the increasing proportion of HRSG06 and HRFG12 CLP with a corresponding lower proportion of LRSG06 and LRFG12 being resected. This resulted in a significantly higher proportion of resected CLP whereby the final pathology confirmed that a surgery was actually indicated. CONCLUSIONS: Over time, there was increasing adherence to the international guidelines for the selection of patients for surgical resection as evidenced by the significantly increasing proportion of HRSG06 and HRFG06 CLPs undergoing surgery. This was associated with a significantly higher proportion of patients with a definitive indication for surgery. These suggested that over time, there was a continuous improvement in our selection of appropriate CLP for surgical treatment.

Exploring MRI based radiomics analysis of intratumoral spatial heterogeneity in locally advanced nasopharyngeal carcinoma treated with intensity modulated radiotherapy.

BACKGROUND: We hypothesized that spatial heterogeneity exists between recurrent and non-recurrent regions within a tumor. The aim of this study was to determine if there is a difference between radiomics features derived from recurrent versus non recurrent regions within the tumor based on pre-treatment MRI. METHODS: A total of 14 T4NxM0 NPC patients with histologically proven "in field" recurrence in the post nasal space following curative intent IMRT were included in this study. Pretreatment MRI were co-registered with MRI at the time of recurrence for the delineation of gross tumor volume at diagnosis(GTV) and at recurrence(GTVr). A total of 7 histogram features and 40 texture features were computed from the recurrent(GTVr) and non-recurrent region(GTV-GTVr). Paired t-tests and Wilcoxon signed-rank tests were carried out on the 47 quantified radiomics features. RESULTS: A total of 7 features were significantly different between recurrent and non-recurrent regions. Other than the variance from intensity-based histogram, the remaining six significant features were either from the gray-level size zone matrix (GLSZM) or the neighbourhood gray-tone difference matrix (NGTDM). CONCLUSIONS: The radiomic features extracted from pre-treatment MRI can potentially reflect the difference between recurrent and non-recurrent regions within a tumor and has a potential role in pre-treatment identification of intra-tumoral radio-resistance for selective dose escalation.

New Advances in Magnetic Resonance Techniques in Abdomen and Pelvis.

This article explores new acquisition methods in magnetic resonance (MR) imaging to provide high spatial and temporal resolution imaging for a wide spectrum of clinical applications in the abdomen and pelvis. We present an overview of some of these advanced MR techniques, such as non-cartesian image acquisition, fast sampling and compressed sensing, diffusion quantification and quantitative MR that can improve data sampling, enhance image quality, yield quantitative measurements, and/or optimize diagnostic performance in the body.

A Circulating miRNA Signature for Stratification of Breast Lesions among Women with Abnormal Screening Mammograms.

Although mammography is the gold standard for breast cancer screening, the high rates of false-positive mammograms remain a concern. Thus, there is an unmet clinical need for a non-invasive and reliable test to differentiate between malignant and benign breast lesions in order to avoid subjecting patients with abnormal mammograms to unnecessary follow-up diagnostic procedures. Serum samples from 116 malignant breast lesions and 64 benign breast lesions were comprehensively profiled for 2,083 microRNAs (miRNAs) using next-generation sequencing. Of the 180 samples profiled, three outliers were removed based on the principal component analysis (PCA), and the remaining samples were divided into training (n = 125) and test (n = 52) sets at a 70:30 ratio for further analysis. In the training set, significantly differentially expressed miRNAs (adjusted p < 0.01) were identified after correcting for multiple testing using a false discovery rate. Subsequently, a predictive classification model using an eight-miRNA signature and a Bayesian logistic regression algorithm was developed. Based on the receiver operating characteristic (ROC) curve analysis in the test set, the model could achieve an area under the curve (AUC) of 0.9542. Together, this study demonstrates the potential use of circulating miRNAs as an adjunct test to stratify breast lesions in patients with abnormal screening mammograms.

Hyperprogressive disease in hepatocellular carcinoma with immune checkpoint inhibitor use: a case series.

Immune checkpoint inhibitors (ICIs) have demonstrated promising results in a variety of advanced cancer types. The phenomenon of hyperprogressive disease (HPD) has only been documented in recent years, however, there have been no reports of HPD in hepatocellular carcinoma. We present a case series of six patients with advanced hepatocellular carcinoma treated with ICIs who demonstrated rapid radiological progression, this was confirmed by comparing tumor growth rates before and during treatment with HPD defined as tumor growth rateratio ≥2. Although ICIs have demonstrated profound efficacy in advanced cancer, they might also be responsible for HPD in a small subset of patients. The ability to predict treatment response to ICI is thus of importance in protecting patients from the deleterious effects of HPD.

SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma.

Purpose Selective internal radiation therapy or radioembolization (RE) shows efficacy in unresectable hepatocellular carcinoma (HCC) limited to the liver. This study compared the safety and efficacy of RE and sorafenib in patients with locally advanced HCC. Patients and Methods SIRveNIB (selective internal radiation therapy v sorafenib), an open-label, investigator-initiated, phase III trial, compared yttrium-90 (90Y) resin microspheres RE with sorafenib 800 mg/d in patients with locally advanced HCC in a two-tailed study designed for superiority/detriment. Patients were randomly assigned 1:1 and stratified by center and presence of portal vein thrombosis. Primary end point was overall survival (OS). Efficacy analyses were performed in the intention-to-treat population and safety analyses in the treated population. Results A total of 360 patients were randomly assigned (RE, 182; sorafenib, 178) from 11 countries in the Asia-Pacific region. In the RE and sorafenib groups, 28.6% and 9.0%, respectively, failed to receive assigned therapy without significant cross-over to either group. Median OS was 8.8 and 10.0 months with RE and sorafenib, respectively (hazard ratio, 1.1; 95% CI, 0.9 to 1.4; P = .36). A total of 1,468 treatment-emergent adverse events (AEs) were reported (RE, 437; sorafenib, 1,031). Significantly fewer patients in the RE than sorafenib group had grade ≥ 3 AEs (36 of 130 [27.7%]) v 82 of 162 [50.6%]; P < .001). The most common grade ≥ 3 AEs were ascites (five of 130 [3.8%] v four of 162 [2.5%] patients), abdominal pain (three [2.3%] v two [1.2%] patients), anemia (zero v four [2.5%] patients), and radiation hepatitis (two [1.5%] v zero [0%] patients). Fewer patients in the RE group (27 of 130 [20.8%]) than in the sorafenib group (57 of 162 [35.2%]) had serious AEs. Conclusion In patients with locally advanced HCC, OS did not differ significantly between RE and sorafenib. The improved toxicity profile of RE may inform treatment choice in selected patients.

Systematic review of the clinical utility and validity of the Sendai and Fukuoka Consensus Guidelines for the management of intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND: This systematic review was performed to assess the clinical utility of the Sendai Consensus Guidelines (SCG) and Fukuoka Consensus Guidelines (FCG) for intraductal papillary mucinous neoplasm (IPMN). METHODS: A computerized search of PubMed was performed to identify all the studies which evaluated the SCG and FCG in surgically resected, histologically confirmed IPMNs. RESULTS: Ten studies evaluating the FCG, 8 evaluating the SCG and 4 evaluating both guidelines were included. In 14 studies evaluating the FCG, out of a total of 2498 neoplasms, 849 were malignant and 1649 were benign neoplasms. Pooled analysis showed that 751 of 1801 (42%) FCG+ve neoplasms were malignant and 599 neoplasms of 697 (86%) FCG-ve neoplasms were benign. PPV of the high risk and worrisome risk groups were 465/986 (47%) and 239/520 (46%) respectively. In 12 studies evaluating the SCG, 1234 neoplasms were analyzed of which 388 (31%) were malignant and 846 (69%) were benign. Pooled analysis demonstrated that 265 of 802 (33%) SCG+ve neoplasms were malignant and 238 of 266 SCG-ve (90%) neoplasms were benign. CONCLUSION: The FCG had a higher positive predictive value (PPV) compared to the SCG. However, the negative predictive value (NPV) of the FCG was slightly lower than that of the SCG. Malignant and even invasive IPMN may be missed according to both guidelines.

Focal Therapy for Prostate Cancer with In-Bore MR-guided Focused Ultrasound: Two-Year Follow-up of a Phase I Trial-Complications and Functional Outcomes.

Purpose To report the safety profile and 2-year functional outcomes of in-bore magnetic resonance (MR)-guided focused ultrasound on single cancer foci in men with prostate cancer. Materials and Methods Ethics approval was obtained from the centralized institutional review board for this prospective single-arm study, and patients provided informed consent. Patients with untreated low-volume low-grade prostate cancer (clinical stage T2a or lower; Gleason score, 3+3; index tumor ≤10 mm3) underwent MR-guided focused ultrasound between July 2011 and February 2013. All patients underwent robotic transperineal mapping biopsy and multiparametric MR imaging. Only those with a maximum of two lesions smaller than 10 mm at mapping biopsy were included. Target areas were sonicated with real-time MR thermometry monitoring, excluding critical areas from the beam path. Serum prostate-specific antigen (PSA) and Expanded Prostate Index Composite (EPIC) scores were obtained at baseline and at 1, 3, 6, 12, 18, and 24 months and were plotted to observe their trend. Mean EPIC subdomain score changes at each serial time point were compared with the baseline score by using paired t tests (level of significance, P < .007). Repeat transperineal biopsy was performed at 6 and 24 months. Results Fourteen men (mean age, 62.8 years; median PSA level, 8.3 ng/mL) underwent treatment, with 12 men completing 2-year follow-up. A median reduction of PSA level by 2.9 ng/mL was observed at 6 months. Seven men had Clavien-Dindo grade 1-2 complications. There was a slight insignificant deterioration of EPIC urinary symptom score (mean increase of 7.8 points compared with baseline, P = .012) noted at 1 month, but it returned to baseline by 3 months. There was a trend to deterioration in sexual function score (mean decrease, 4.4 points; P = .04 [not significant]) that normalized at 3 months. There was no significant change in EPIC subdomain scores from baseline over the 24 months. At 6-month template biopsy, one man had cancer with a Gleason score greater than 6; at 24 months, three men had cancer with a Gleason score greater than 6. Conclusion MR-guided focused ultrasound is technically feasible for focal prostate ablation and appears to have a favorable early safety and functional profile. Further clinical trials are necessary to establish oncologic efficacy. © RSNA, 2017 Online supplemental material is available for this article.

Single administration of Selective Internal Radiation Therapy versus continuous treatment with sorafeNIB in locally advanced hepatocellular carcinoma (SIRveNIB): study protocol for a phase iii randomized controlled trial.

BACKGROUND: Approximately 20 % of hepatocellular carcinoma (HCC) patients diagnosed in the early stages may benefit from potentially curative ablative therapies such as surgical resection, transplantation or radiofrequency ablation. For patients not eligible for such options, prognosis is poor. Sorafenib and Selective Internal Radiation Therapy (SIRT) are clinically proven treatment options in patients with unresectable HCC, and this study aims to assess overall survival following either SIRT or Sorafenib therapy for locally advanced HCC patients. METHODS: This investigator-initiated, multi-centre, open-label, randomized, controlled trial will enrol 360 patients with locally advanced HCC, as defined by Barcelona Clinic Liver Cancer stage B or stage C, without distant metastases, and which is not amenable to immediate curative treatment. Exclusion criteria include previous systemic therapy, metastatic disease, complete occlusion of the main portal vein, or a Child-Pugh score of >7. Eligible patients will be randomised 1:1 and stratified by centre and presence or absence of portal vein thrombosis to receive either a single administration of SIRT using yttrium-90 resin microspheres (SIR-Spheres®, Sirtex Medical Limited, Sydney, Australia) targeted at HCC in the liver by the trans-arterial route or continuous oral Sorafenib (Nexavar®, Bayer Pharma AG, Berlin, Germany) at a dose of 400 mg twice daily until disease progression, no further response, complete regression or unacceptable toxicity. Patients for both the Sorafenib and SIRT arms will be followed-up every 4 weeks for the first 3 months and 12 weekly thereafter. Overall survival is the primary endpoint, assessed for the intention-to-treat population. Secondary endpoints are tumour response rate, time-to-tumour progression, progression free survival, quality of life and down-staging to receive potentially curative therapy. DISCUSSION: Definitive data comparing these two therapies will help to determine clinical practice in the large group of patients with locally advanced HCC and improve outcomes for such patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01135056 , first received 24, May 2010.

Phase Ib/II randomized, open-label study of doxorubicin and cyclophosphamide with or without low-dose, short-course sunitinib in the pre-operative treatment of breast cancer.

BACKGROUND: Prolonged anti-angiogenic therapy destroys tumor vasculature, whereas vascular-normalizing doses may enhance intra-tumoral drug delivery. We hypothesize that low-dose, short-course sunitinib normalizes vasculature, enhancing chemotherapy efficacy. PATIENTS AND METHODS: In phase Ib, treatment-naïve breast cancer patients received four cycles of pre-operative doxorubicin/cyclophosphamide, with sunitinib before each cycle. The optimal dose of sunitinib leading to tumor vessel normalization on immunohistochemistry was identified. In phase II, subjects were randomized to chemotherapy alone or chemotherapy plus sunitinib at the recommended phase II dose (RP2D). Primary endpoint was pathological complete response (pCR) rate. Tumor and functional imaging biomarkers were evaluated serially. RESULTS: In phase Ib (n=9), sunitinib 12.5 mg daily for 7 days before each chemotherapy was established as RP2D. In phase II, patients receiving chemotherapy plus sunitinib (n=24) had similar pCR rates (5.0% versus 4.3%, p=1.00), but a higher incidence of chemotherapy dose delays (33.3% versus 8.7%, p=0.04), compared to those receiving chemotherapy alone (n=25). The addition of sunitinib to chemotherapy significantly increased vascular normalization index (VNI) and decreased lymphatic vessel density (D2-40) on immunohistochemistry [VNI:25.50±27.94% versus 49.29±31.84%, p=0.034; D2-40:3.29±2.70 versus 1.29±1.54, p=0.014, baseline versus post-cycle 1], and improved perfusion on DCE-MRI (Ktrans:12.6±9.6 mL/100 g/min versus 16.3±10.7 mL/100 g/min, baseline versus post-cycle 1, p=0.015). Conversely, immunohistochemical and DCE-MRI parameters were not significantly altered by chemotherapy alone. CONCLUSION: Low-dose, short-course sunitinib prior to anthracycline-based chemotherapy in breast cancer patients did not improve pCR and increased chemotherapy dose delays. However, the addition of sunitinib induced compelling pharmacodynamic evidence of vascular normalization. Further studies with alternative cytotoxic regimens should be explored.

Preoperative platelet-to-lymphocyte ratio improves the performance of the international consensus guidelines in predicting malignant pancreatic cystic neoplasms.

INTRODUCTION: To determine if neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were predictive of malignancy in pancreatic cystic neoplasms (PCN) and if these improved the performance of the international consensus guidelines (ICG) in the initial triage of these patients. METHODS: 318 patients with surgically-treated suspected PCN were retrospectively reviewed. Malignant neoplasms were defined as neoplasms harbouring invasive carcinoma. The optimal cut-off for NLR and PLR were determined by plotting the receiver operating characteristics (ROC) curves of NLR/PLR in predicting malignant PCN and utilizing the Youden index. RESULTS: The optimal NLR and PLR cut-offs were determined to be 3.33 and 205, respectively. Univariate analyses demonstrated that symptomatic PCNs, age, obstructive jaundice, presence of solid component, dilatation of main pancreatic duct ≥10 mm, high NLR and high PLR were predictive of a malignant PCN. Multivariate analyses demonstrated that obstructive jaundice, presence of solid component, MPD ≥10 mm and high PLR but not NLR were independent predictors of a malignant PCN. A high PLR significantly predicted invasive carcinoma in patients classified within the ICG(HR) group. Comparison between the ROC curves of the ICG versus ICG plus high PLR in predicting malignant PCN demonstrated a significant improvement in the accuracy of the ICG when PLR was included [AUC 0.784 (95% CI: 0.740-0.829) vs AUC 0.822 (95% CI: 0.772-0.872) (p = 0.0032)]. CONCLUSIONS: High PLR is an independent predictor of malignancy in PCN. The addition of PLR as a criterion to the ICG improved the accuracy of these guidelines in detecting invasive neoplasms.

National Cancer Centre Singapore Consensus Guidelines for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the 6th most common cancer in the world, but the second most common cause of cancer death. There is no universally accepted consensus practice guidelines for HCC owing to rapid developments in new treatment modalities, the heterogeneous epidemiology and clinical presentation of HCC worldwide. However, a number of regional and national guidelines currently exist which reflect practice relevant to the epidemiology and collective experience of the consensus group. In 2014, clinicians at the multidisciplinary Comprehensive Liver Cancer Clinic (CLCC) at the National Cancer Centre Singapore (NCCS) reviewed the latest published scientific data and existing international and regional practice guidelines, such as those of the National Comprehensive Cancer Network, American Association for the Study of Liver Diseases and the Asian Pacific Association for the Study of the Liver, and modified them to reflect local practice. These would serve as a template by which treatment outcomes can be collated and benchmarked against international data. The NCCS Consensus Guidelines for HCC have been successfully implemented in the CLCC since their publication online on 26(th) September 2014, and the guidelines allow outcomes of treatment to be compared to international data. These guidelines will be reviewed periodically to incorporate new data.