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PDF file - 83K, JAK1 and JAK3 mutation status in NKTCL cases

PDF file - 110K, Non-synonymous somatic mutations identified in the Discovery set of four NKTCL cases

PDF file - 75K, Sequence analysis summary of tumor and blood samples from four NKTCL cases

PDF file - 74K, Primer sets used for Sanger sequencing and HRM analysis

PDF file - 185K, Representative HRM curves of a NKTCL case confirmed as heterozygous JAK3A573V mutation

Supplementary Figure from Co-Targeting of MDM2 and CDK4/6 with Siremadlin and Ribociclib for the Treatment of Patients with Well-Differentiated or Dedifferentiated Liposarcoma: Results from a Proof-of-Concept, Phase Ib Study

Purpose:Well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma are characterized by co-amplification of the murine double minute-2 (MDM2) and cyclin-dependent kinase-4 (CDK4) oncogenes. Siremadlin, a p53–MDM2 inhibitor, was combined with ribociclib, a CDK4/6 inhibitor, in patients with locally advanced/metastatic WDLPS or DDLPS who had radiologically progressed on, or despite, prior systemic therapy.Patients and Methods:In this proof-of-concept, phase Ib, dose-escalation study, patients received siremadlin and ribociclib across different regimens until unacceptable toxicity, disease progression, and/or treatment discontinuation: Regimen A [4-week cycle: siremadlin once daily (QD) and ribociclib QD (2 weeks on, 2 weeks off)], Regimen B [3-week cycle: siremadlin once every 3 weeks; ribociclib QD (2 weeks on, 1 week off)], and Regimen C [4-week cycle: siremadlin once every 4 weeks; ribociclib QD (2 weeks on, 2 weeks off)]. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of siremadlin plus ribociclib in one or more regimens.Results:As of October 16, 2019 (last patient last visit), 74 patients had enrolled. Median duration of exposure was 13 (range, 1–174) weeks. Dose-limiting toxicities occurred in 10 patients, most of which were Grade 3/4 hematologic events. The RDE was siremadlin 120 mg every 3 weeks plus ribociclib 200 mg QD (Regimen B). Three patients achieved a partial response, and 38 achieved stable disease. One patient (Regimen C) died as a result of treatment-related hematotoxicity.Conclusions:Siremadlin plus ribociclib demonstrated manageable toxicity and early signs of antitumor activity in patients with advanced WDLPS or DDLPS.

Supplementary Data from Co-Targeting of MDM2 and CDK4/6 with Siremadlin and Ribociclib for the Treatment of Patients with Well-Differentiated or Dedifferentiated Liposarcoma: Results from a Proof-of-Concept, Phase Ib Study

Angiosarcoma (AS) is a rare disease with a dismal prognosis. The treatment landscape and prognostic factors for advanced AS, including locally advanced, unresectable, and metastatic disease remain elusive. The Asian Sarcoma Consortium is an international collaborative effort to understand the sarcoma treatment landscape in Asia. We undertook a retrospective chart review of AS patients seen in 8 sarcoma academic centers across Asia. Patients with complete clinical, treatment, and follow‐up data were enrolled. Overall, 276 advanced AS patients were included into this study; 84 (30%) of the patients had metachronous metastatic AS. The median age was 67 y; primary sites of AS was cutaneous in 55% and visceral in 45% of patients. In total, 143 (52%) patients received at least 1 line of systemic chemotherapy. The most common first‐line chemotherapy regimen used was paclitaxel (47.6%) followed by liposomal doxorubicin (19.6%). The median overall survival (OS) was 7.8 mo. Significant prognostic factors for OS included age > 65 (hazard ratio (HR) 1.54, P = .006), male gender (HR 1.39, P = .02), and a cutaneous primary AS site (HR 0.63, P = .004). The median progression‐free survival (PFS) for first‐line chemotherapy was 3.4 mo. PFS for single vs combination or paclitaxel vs liposomal doxorubicin chemotherapy regimens were comparable. This study provides an insight into the treatment patterns and prognostic factors of advanced AS patients in Asia. Prognosis of advanced AS remains poor. Data from this study serve as a benchmark for future clinical study design., With a total of 276 advanced angiosarcoma patients, we provided the complete clinicopathological demographics, treatment patterns, and prognostic outcomes of advanced angiosarcoma in Asia.

Background Neoadjuvant imatinib for gastrointestinal stromal tumors (GIST) of the rectum can reduce, but may not eliminate, risk of surgical morbidity from permanent bowel diversion. We sought to evaluate the cost-effectiveness of alternative strategies in rectal GIST patients requiring abdominoperineal resection following neoadjuvant imatinib. Methods We developed a Markov model using a healthcare payers’ perspective to estimate costs in 2017 Singapore dollars (SGD) and quality adjusted life years (QALYs) for upfront abdominoperineal resection (UAPR) versus continued imatinib until progression (CIUP) following 1 year of neoadjuvant imatinib. Transition probabilities and utilities were obtained from published data, and costs were estimated using data from the National Cancer Centre Singapore. Deterministic and probabilistic sensitivity analyses were conducted to probe model uncertainty. Incremental cost-effectiveness ratio below SGD 50,000 per QALY gained was considered cost-effective. Results In the base case, UAPR dominates CIUP being both more effective (8.66 QALYS vs 5.43 QALYs) and less expensive (SGD 312,627 vs SGD 339,011). These estimates were most sensitive to 2 variables, utility of abdominoperineal resection and annual recurrence probability post-abdominoperineal resection. However, simultaneously varying the values of these variables to maximally favor CIUP did not render it the more cost effective strategy at willingness to pay (WTP) of SGD 50,000. In probabilistic sensitivity analysis, UAPR had probability of being cost-effective compared with CIUP greater than 95%, reaching 100% at WTP SGD 10,000. Conclusion UAPR is more effective and less costly than CIUP for patients with rectal GIST requiring abdominoperineal resection following neoadjuvant imatinib, and is the strategy of choice in this setting.

A 41-yr-old lady with abnormal uterine bleeding underwent total abdominal hysterectomy. Histologic assessment revealed an endometrial stromal sarcoma (ESS) with minimal cytologic atypia and low mitotic count (up to 7/10 high-power fields) with only focal myxoid areas, morphologically corresponding to a low-grade ESS. Immunohistochemical stains showed cyclin D1 and CD10 positivity, and negative staining for CD117 and progesterone receptor. This tumor was clinically aggressive and recurred 6 mo later. The patient died 19 mo following initial diagnosis. Molecular analysis revealed a ZC3H7B (exon 10)-BCOR (exon 7) gene fusion. Subsequent BCOR immunohistochemistry was weakly positive. ESS with ZC3H7B-BCOR gene fusion is classified as a low-grade ESS in some classification schemes, and is also characterized as being typically myxoid. This report supports emerging evidence that ESS with ZC3H7B-BCOR gene fusion may have an aggressive clinical course in spite of its low-grade histology. This report further expands the morphologic spectrum of ZC3H7B-BCOR fusion ESS to include nonmyxoid histology. Finally, this report underlines the value of molecular analysis in the proper classification of this aggressive tumor with deceptive low-grade histology.

Contemporary data of peripheral T-cell lymphoma (PTCL) and natural-killer/T-cell lymphoma (NKTL) patients treated with ifosfamide, carboplatin and etoposide (ICE) are limited.We performed a retrospective analysis to estimate outcomes of ICE-treated PTCL and NKTL patients at three tertiary cancer centres in Singapore.Patients were identified through lymphoma databases from National Cancer Centre Singapore (NCCS), National University Hospital, Singapore (NUHS), and Singapore General Hospital (SGH). Responses and survival outcomes were determined from electronic medical records. A total of 75 patients with a median age of 50 were included. ICE was used as first-line treatment in 14 patients (19%) and as subsequent lines of treatment in 61 patients (81%). The overall response rates (ORR) for all patients was 63% (40% complete response [CR]). The ORR and CR in the first line were 86% and 64% respectively. At a median follow-up duration of 71.0 months, the median progression-free (PFS) and overall survival (OS) for all patients were 4.4 months (95%CI, 2.7-6.0) and 16 months (95%CI, 8.3-45.4) respectively.In summary, ICE showed high ORR but poor PFS in relapsed/refractory PTCL and NKTL. ORR of ICE in the first line setting appears better than real-world CHOP data and warrants further study.

Angiosarcomas are rare, clinically aggressive tumors with limited treatment options and a dismal prognosis. We analyzed angiosarcomas from 68 patients, integrating information from multiomic sequencing, NanoString immuno-oncology profiling, and multiplex immunohistochemistry and immunofluorescence for tumor-infiltrating immune cells. Through whole-genome sequencing (n = 18), 50% of the cutaneous head and neck angiosarcomas exhibited higher tumor mutation burden (TMB) and UV mutational signatures; others were mutationally quiet and non–UV driven. NanoString profiling revealed 3 distinct patient clusters represented by lack (clusters 1 and 2) or enrichment (cluster 3) of immune-related signaling and immune cells. Neutrophils (CD15(+)), macrophages (CD68(+)), cytotoxic T cells (CD8(+)), Tregs (FOXP3(+)), and PD-L1(+) cells were enriched in cluster 3 relative to clusters 2 and 1. Likewise, tumor inflammation signature (TIS) scores were highest in cluster 3 (7.54 vs. 6.71 vs. 5.75, respectively; P < 0.0001). Head and neck angiosarcomas were predominant in clusters 1 and 3, providing the rationale for checkpoint immunotherapy, especially in the latter subgroup with both high TMB and TIS scores. Cluster 2 was enriched for secondary angiosarcomas and exhibited higher expression of DNMT1, BRD3/4, MYC, HRAS, and PDGFRB, in keeping with the upregulation of epigenetic and oncogenic signaling pathways amenable to targeted therapies. Molecular and immunological dissection of angiosarcomas may provide insights into opportunities for precision medicine.

Peripheral blood indices of systemic inflammation such as the neutrophil-lymphocyte ratio (NLR) have been shown to be prognostic in various cancers. We aim to investigate the clinical significance of these indices in patients with soft tissue sarcoma (STS). Seven hundred and twelve patients with available blood counts at diagnosis and/or metastatic relapse were retrospectively examined. An optimal cutoff for NLR-high (>2.5) in predicting overall survival (OS) was determined using receiver operating curve analyses. Survival analyses were performed using the Kaplan-Meier method and multivariate Cox proportional models. Our results show that NLR was significantly higher in patients with distant metastasis at diagnosis (n = 183) compared to those without (n = 529) (median: 4.36 vs 2.85, p p = 0.0003). In multivariate analysis, NLR-high was the only consistent factor independently associated with both worse OS (HR 1.53, 95% CI 1.10–2.13, p = 0.0112) and relapse-free survival (HR 1.41, 95% CI 1.08–1.85, p = 0.0125) in localized disease, as well as OS (HR 1.82, 95% CI 1.16–2.85, p = 0.0087) in metastatic/unresectable disease. In conclusion, high NLR is an independent marker of poor prognosis among patients with STS.

Background The advent of tyrosine kinase inhibitors as adjuvant therapy has revolutionized the management of GIST and emphasized the need for accurate prognostication systems. Numerous prognostication systems have been proposed for GIST but at present it remains unknown which system is superior. The present systematic review aims to summarize current prognostication systems for primary treatment-naive GIST. Methods A literature review of the Pubmed and Embase databases was performed to identify all published articles in English, from the 1st January 2002 to 28th Feb 2017, reporting on clinical prognostication systems of GIST. Results Twenty-three articles on GIST prognostication systems were included. These systems were classified as categorical systems, which stratify patients into risk groups, or continuous systems, which provide an individualized form of risk assessment. There were 16 categorical systems in total. There were 4 modifications of the National Institute of Health (NIH) system, 2 modifications of Armed Forces Institute of Pathology (AFIP) criteria and 3 modifications of Joensuu (modified NIH) criteria. Of the 7 continuous systems, there were 3 prognostic nomograms, 3 mathematical models and 1 prognostic heat/contour maps. Tumor size, location and mitotic count remain the main variables used in these systems. Conclusion Numerous prognostication systems have been proposed for the risk stratification of GISTs. The most widely used systems today are the NIH, Joensuu modified NIH, AFIP and the Memorial Sloan Kettering Cancer Center nomogram. More validation and comparison studies are required to determine the optimal prognostication system for GIST.

Background Acral melanoma (AM) and mucosal melanoma (MM) make up more than half of melanomas in Asia but comprise only 5% of cases in Caucasians, where cutaneous melanoma (CM) predominates. AM and MM are thought to be genetically and biologically distinct from CM. We report the characteristics and outcomes of melanoma patients from the National Cancer Centre Singapore. Methods Case records of 210 patients treated between 2002 and 2014 were reviewed. Results Median follow-up was 2.5 years. CM, AM and MM made up of 37.6%, 33.8% and 16.2% of cases, respectively, with 6.2% each having ocular melanoma and unknown primary. Caucasians made up 16.2% of patients, accounting for 36.7% of CM but only 2.8 of AM and 2.9% of MM. Patients with MM (2.9% stage I, 14.7% stage IV) presented with higher American Joint Committee on Cancer (AJCC) stage than those with AM (16.9% stage I, 5.6% stage IV) or CM (24.1% stage I, 8.9% stage IV) (P = 0.01). Median overall survival (OS) was 5.7 years for all patients, and 1.0 year for metastatic disease. Considering stage I–III disease, multivariable Cox regression analysis demonstrated age ≥60 years and higher stage to be independent adverse prognostic factors for RFS and OS. Sentinel lymph node biopsy, undertaken for 56 stage I–III patients (25 AM, 31 CM) did not influence outcome. Conclusion Our study reinforces the known unique clinicopathologic features of melanomas in Asians where AM and MM predominate. Age and stage remain the most critical prognostic factors across all subtypes.

Objective The primary objective of this study is to prospectively evaluate the role of procalcitonin (PCT) in distinguishing infectious fever from noninfectious fever (NIF) among febrile lymphoma patients. The secondary objective is to evaluate the usefulness of PCT in distinguishing among bloodstream infections (BSI), local infections and unidentified infections (LIUI), and NIF. Methods Patients with lymphoma and fever were prospectively recruited between August 2014 and November 2015. PCT was measured within 24 hours of fever onset (PCT1) and 24-72 hours thereafter (PCT2). The higher PCT value between PCT1 and PCT2 was also documented (PCTmax ). PCT levels (PCT1, PCT2, and PCTmax ) were compared for BSI, LIUI, and NIF. In addition, the difference between PCT1 and PCT2 was evaluated in patients with complete data on both PCT1 and PCT2. Results Of 108 eligible patients, 12 were diagnosed with BSI, 83 with LIUI, and 13 with NIF. PCTmax was statistically different between the infectious fever (BSI and LIUI combined) and NIF groups (median PCTmax : 0.44 ng/ml vs 0.19 ng/ml; p=0.026). PCT1 was not statistically different for patients with BSI, LIUI, and NIF (p=0.217). However, PCT2 and PCTmax were significantly higher in patients with BSI compared to those with NIF (p=0.026 and 0.002, respectively). Meanwhile, patients with BSI have significantly higher PCTmax values than those with LIUI (p=0.034). Among 90 cases with complete data on both PCT1 and PCT2, PCT2 was significantly higher than PCT1 in patients with BSI (median PCT: 0.98 ng/ml vs 0.47 ng/ml; p=0.045) and patients with LIUI (median PCT: 0.43 ng/ml vs 0.24 ng/ml; p=0.004), while not significant in patients with NIF (p=0.374). Conclusion Two separate PCT measurements can differentiate between infectious fever and NIF and predict for BSI in lymphoma patients with fever.

Aim To review our experience in the management of retroperitoneal sarcomas (RPSs) in a single institution, with a predominantly Asian population, and identify associated prognostic factors for overall survival (OS), disease-free survival (DFS) and local recurrence. Materials and methods All RPSs diagnosed and managed at our center between January 2000 and March 2014 were included. Exclusion criteria included patients whose medical records were untraceable and patients who underwent biopsy but did not undergo resection. The variables studied were age, gender, histological subtype, tumor size, tumor grade, surgical margins, type of presentation of tumor (primary or recurrent) and presence of contiguous organ resection. The primary outcome measured was OS. Results Eighty-five patients underwent resection of RPS with curative intent. Eight patients underwent adjuvant chemotherapy and 15 patients underwent radiotherapy. The median DFS was 21 months (range: 0–146) and median OS was 45 months (range: 1–233). On univariate analysis, resection margin (P = 0.04), tumor grade (P = 0.011) and type of presentation of tumor (P = 0.007) were found to significantly affect OS. Patients with tumor adherent to contiguous organs had a greater OS as compared to patients with tumor invasive into the contiguous organs (P = 0.02). Conclusion An aggressive surgical approach in primary and recurrent RPS is associated with good OS. Complete resection, with contiguous organ resection if necessary should be performed to achieve microscopically negative surgical margins to allow for long-term survival. However, tumor biology remains the main determinant for OS.

Aim A nomogram for prediction of 12-year sarcoma-specific survival has been developed based on patients with soft tissue sarcomas treated in Memorial Sloan Kettering Cancer Centre (MSKCC). We aim to evaluate the predictive accuracy of the MSKCC sarcoma nomogram in a cohort of patients treated at an Asian institution. This has not been validated in an Asian population and thus its universal applicability remains unproven. Materials and methods Between 1990 and 2013, 840 adult patients underwent treatment for primary soft tissue sarcoma (STS) at the National Cancer Centre Singapore. Patients who presented with locally recurrent or metastatic disease were excluded from the analysis. The variables included in the MSKCC nomogram included age at diagnosis, tumor size, histologic grade, histologic subtype, depth and site. A total of 399 patients were left for analysis. The nomogram was validated by assessing its extent of discrimination and level of calibration. Results All patients had deep tumors. Disease occurred most commonly in the lower extremity (n = 149 [37.3%]), the most common histologic subtype was “Others” (angiosarcoma, ewing's sarcoma, endometrial stromal sarcoma, sarcoma NOS [not otherwise specified] and rhabdomyosarcoma). Sixty-four percent of all patients had high-grade tumors while 36% had low-grade tumors. The median patient age at diagnosis was 54 years (range: 17–88 years). The median follow up time for all patients and surviving patients were 29 (range: 1–174) and 33 (range: 1–157) months, respectively. The observed 5- and 10-year sarcoma-specific survival were 55% and 33%, respectively. The concordance index was 0.71. For level of calibration, the observed correspondence between predicted and actual outcomes suggest that the MSKCC nomogram generally predicts well for patients with higher survival probability, but consistently overpredicts survival for the other groups, in our cohort of patients. Conclusion The MSKCC sarcoma nomogram was found to be accurate in terms of extent of discrimination. In terms of level of calibration, it generally predicts well for patients with higher survival probability, but consistently overpredicts survival for the other groups in our population.

Aim Benefit of adjuvant imatinib therapy following curative resection in patients with intermediate-risk gastrointestinal stromal tumor (GIST) is unclear. GIST-specific exon mutations, in particular exon 11 deletions, have been shown to be prognostic. We hypothesize that specific KIT mutations may improve risk stratification in patients with intermediate-risk GIST, identifying a subgroup of patients who may benefit from adjuvant therapy. Methods In total, 142 GIST patients with complete clinicopathologic and mutational data from two sites were included. Risk classification was based on the modified National Institute of Health (NIH) criteria. Results In this cohort, 74% (n = 105) of patients harbored a KIT mutation; 61% (n = 86) were found in exon 11 of which nearly 70% were KIT exon 11 deletions (n = 60). A total of 18% (n = 25) of cases were classified as having intermediate-risk disease. Univariate analysis confirmed tumor size, mitotic index, nongastric origin, presence of tumor rupture and modified NIH criteria were adversely prognostic for relapse-free survival (RFS). Among KIT/PDGFRA mutants, KIT exon 11 deletions had a significantly worse prognosis (hazard ratio 2.31; 95% confidence interval, 1.30–4.10; P = 0.003). Multivariate analysis confirmed KIT exon 11 deletion (P = 0.003) and clinical risk classification (P < 0.001) as independent adverse prognostic factors for RFS. Intermediate-risk patients harboring KIT exon 11 deletions had RFS outcomes similar to high-risk patients. Conclusion The presence of KIT exon 11 deletion mutation in patients with intermediate-risk GIST is associated with an inferior clinical outcome with RFS similar to high-risk patients.

Background Gastrointestinal stromal tumours (GISTs) represent the most common mesenchymal tumour of the gastrointestinal tract. Although the efficacy of targeted therapy cannot be over-emphasized, surgery remains the only curative primary treatment for patients with localized disease. The median size of GIST at diagnosis is approximately 5–7 cm; however, it is not uncommon for tumours to be as large as 30–40 cm and involving multiple viscera. Methods Data were retrospectively collected from patients with GISTs treated at the Singapore General Hospital and the National Cancer Centre Singapore over a 15-year period. Standard resection of GIST without any additional organ removal was termed as a single organ resection (SOR). If the tumour was adjacent to another organ, necessitating the removal of more than one organ, the procedure was defined as a multivisceral resection (MVR). We aim to evaluate the role of MVR in the management of large GISTs. Results A total of 187 patients underwent curative surgery for GIST between January 2000 and January 2014. Of the 187 patients, 40 (21%) underwent MVR whereas 147 (79%) had SOR. Patients in the MVR group had significantly larger tumour sizes (P

Background Recent studies have demonstrated that the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are prognostic for various malignancies; however, there are limited data to date demonstrating their usefulness for gastrointestinal stromal tumors (GISTs). The aim of this study was to determine whether NLR and PLR are prognostic for GIST. Methods Three hundred patients who underwent operative resection for primary localized GIST with preoperative results for neutrophil, platelet, and lymphocyte counts available were retrospectively reviewed. Optimal cutoff values for high NLR (≥3.0) and PLR (≥275) in predicting recurrence-free survival (RFS) were determined. Prognostic factors of RFS were determined using univariate and multivariate Cox regression analyses for the 266 patients who did not receive adjuvant imatinib. Results On univariate analyses, tumor size, mitotic count, location, and both a high NLR and PLR were significant prognostic indicators of decreased RFS (hazard ratio [HR], 2.89 [95% CI; 1.609–5.179 P Conclusion High NLR and PLR were independent prognostic factors of RFS in GIST. NLR and PLR would be useful as a preoperative prognostic tool and its incorporation into current prognostication systems improved their accuracy.

Introduction The role of surveillance imaging (SI) in patients with peripheral T-cell lymphoma (PTCL) in first complete remission (CR1) is unclear. Materials and Methods Patients with PTCL were identified through prospectively maintained T-cell lymphoma databases from the National Cancer Centre Singapore/Singapore General Hospital and Weill-Cornell Medical College after institutional review board approval. Patients with leukemia or indolent, composite, and cutaneous lymphomas were excluded. The patients' medical records were retrospectively reviewed to determine the frequency and type of SI used. Of those with relapse, the method of relapse detection and data on symptoms, signs, and elevated lactate dehydrogenase LDH were extracted. Results A total of 338 patients were included in the present study. In the first year after achieving CR1, patients had an average of 1.2 and a median of 1 SI performed (range, 0-4). In the second year after achieving CR1, they had an average of 0.78 and a median of 1 SI performed (range, 0-4). Of the 135 patients who achieved CR1, 61 (45%) developed a relapse. Relapses were detected before SI in 48 (84%), and 9 patients had relapses detected during routine SI. Of the 9 patients whose relapses were detected during planned SI, only 3 did not have any symptoms or signs suggestive of relapsed disease. Of these 3 patients, 2 had angioimmunoblastic T-cell lymphoma and 1 had natural killer/T-cell lymphoma. Conclusion Most PTCL relapses were detected before planned SI, and most patients had symptoms with relapse. Only 3 patients (5.2%) were completely asymptomatic at relapse, suggesting a limited utility of routine imaging for detecting PTCL relapses.

Primary mediastinal large B‐cell lymphoma (PMBCL) is a distinct clinico‐pathological subtype of diffuse large B‐cell lymphoma with unclear prognostic factors and limited clinical data. Optimal treatment and role for radiotherapy is not fully defined. We performed a multicenter retrospective review of 124 patients with newly diagnosed PMBCL between 2001 and 2016. Treatment regimens were R‐CHOP (n = 41), R‐CHOP + RT (n = 37), and DA‐EPOCH‐R (n = 46). 6% (n = 3) in the DA‐EPOCH‐R group received RT. With a median follow up of 45 months, the overall 5‐year OS and PFS was 89.4% and 82.4%, respectively. The type of chemo‐radiotherapy regimen, B symptoms and Ann‐Arbor staging showed a significant association with OS on univariate analysis but only B symptoms remained prognostic (P = 0.012) after multivariate analysis. The chemo‐radiotherapy regimen, Japanese IPI and Ann‐Arbor stage was significantly associated with PFS in univariate analysis, but only chemo‐radiotherapy regimen remained significant (P = 0.02) after multivariate analysis. Patients who received R‐CHOP + RT or DA‐EPOCH‐R had better PFS than those receiving R‐CHOP alone, with 5‐year PFS of 90% vs 88.5% vs 56%, respectively (P = 0.02). In the subgroup analysis of patients with bulk (n = 71), R‐CHOP alone (n = 21) had inferior 5‐year PFS 56.6% compared to those who received R‐CHOP + RT (n = 23) 91.3% or DA‐EPOCH‐R (n = 27) 92.6% (P = 0.007). In contrast, in patients without bulk (n = 42), there was no impact of treatment regimen on PFS (P = 0.25). In conclusion, R‐CHOP + RT and DA‐EPOCH‐R provide excellent outcomes in patients with PMBCL. In patients with bulky disease, the use of DA‐EPOCH‐R may be preferable as it allows omission of RT without reduction in efficacy.

Sarcomas are rare mesenchymal malignancies arising in the soft tissues or bone that are known to be genetically diverse and notoriously difficult to treat. Advances in genomics fueled by massively parallel methods such as next-generation sequencing and array technologies have facilitated integrative analyses of genetic alterations with expression and clinical data, heralding opportunities for leveraging targeted therapies in the management of this challenging family of diseases. This chapter discusses how genomic progress has elevated understanding of the molecular mechanisms of sarcoma and its association with heritable cancer predisposition syndromes as well as the therapeutic implications consequent to this new knowledge.

PURPOSE: Gastrointestinal stromal tumors (GISTs) are characterized by primary mutations (PM) in KIT or PDGFRA genes. Under pharmacological pressure secondary mutations (SM) develop resulting in resistance to treatment. Our group developed a multiplex-amplicon sequencing assay that can detect PM and SM simultaneously in the plasma samples of patients with GIST, at a variant allele frequency of 0.1%. This assay was also designed to optimize detection of exon 11 mutations. PATIENTS AND METHODS: The assay was applied on 238 plasma samples obtained from 65 GIST patients. Clinical data and plasma samples were obtained from a prospective institutional database. Among the 65 patients, 34 had metastatic disease, 4 were on neoadjuvant treatment and 27 had curative surgery followed by adjuvant treatment or surveillance. There were no prespecified timepoints of plasma collection in this study. CtDNA results were correlated with clinical and radiological data. RESULTS: Overall, there was 89% concordance in detection of exon 11 mutations in tissue and plasma. 100% concordance was demonstrated for exons 9,13 and 17. The assay had a sensitivity of 75% and specificity of 94% in detecting mutations in the appropriate clinical context in the metastatic setting. Secondary mutations were detected in the appropriate clinical settings as well. In the metastatic cohort, ctDNA levels were able to correlate with disease trajectory i.e. levels decrease with response to treatment and increase with disease progression. CONCLUSION: This assay is a promising tool that can reliably and accurately detect ctDNA in GIST patients, especially the traditionally difficult exon 11 mutations. Once validated in a larger, prospective setting, this can potentially establish ctDNA as a non invasive biomarker in monitoring disease trajectory in GIST patients.

Natural-killer/T-cell lymphoma (NKTL) is a rare subset of non-Hodgkin lymphoma that demonstrates a unique geographic distribution, with higher prevalence in Asia compared to the West1. While cure remains achievable in early-stage disease, the prognosis for advanced-stage NKTL is dismal2. Recently, some progress has been made in uncovering the molecular pathogenesis of NKTL. In a genome-wide association study, strong correlations between HLA-DPB1 single-nucleotide polymorphisms and NKTL susceptibility were discovered, implicating altered antigen processing and presentation to CD4-positive T-lymphocytes in this Epstein-Barr virus (EBV)-associated malignancy3. Next generation sequencing also revealed recurrent somatic mutations such as TP53, JAK3, STAT3 and DDX3X in NKTL4,5. In this paper, we report a pair of male siblings from a non-consanguineous Chinese family who were diagnosed with NKTL, and provide initial evidence for novel recessive germline mutations in FAM160A1 identified through next-generation sequencing. The index patient was 35 years old, when he presented with nasal blockage in March 2013. 18-FDG-PET/CT imaging revealed an 18-FDG-avid nasal mass infiltrating into the palate, as well as enlarged cervical lymph nodes. Biopsy of the mass showed abnormal lymphoid cells positive for CD56 by immunohistochemistry (IHC) as well as EBV-encoded RNA (EBER) by in-situ hybridization. He was diagnosed with stage IIA extranodal NKTL, nasal type, and treated with 4 cycles of bortezomib-GIFOX (gemcitabine, ifosfamide and oxaliplatin) as part of a clinical trial followed by radiotherapy to the nasal region. He had primary-refractory disease and was further treated with 4 cycles of SMILE (dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide) followed by high-dose chemotherapy and autologous stem cell transplantation. He progressed and received ruxolitinib off-label, followed by RAD001 (mTOR inhibitor) and LBH589B (histone deacetylase inhibitor) as part of another clinical trial. He then had radiotherapy to an ulcerating penile lesion before he died of progressive disease 27 months after diagnosis (Supplementary Table 1). His younger brother was 18 years old, when diagnosed with NKTL affecting the nasal floor in 1998 following a bout of epistaxis. He received 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with high-dose methotrexate and went into complete remission. Three years later he was diagnosed with chronic myeloid leukemia, for which he received hydroxyurea. In 2004, he had a relapse of NKTL and received ESHAP (etoposide, prednisolone, cytarabine and cisplatin), total body irradiation and allogeneic bone marrow transplant. He died of transplant-related complications 6 years from diagnosis. These siblings have an older brother unaffected by any hematological malignancy. Their father died of a non-malignant condition in his fifties and their mother remains well at the age of 68 years. Among their first-degree relatives, none were known to be inflicted with hematologic malignancies (Fig. ​(Fig.11). Open in a separate window Fig. 1 Clinical characterization of brothers with familial NKTL. a 18-FDG-PET/CT image depicting a large nasal mass infiltrating into the palate, of which biopsy showed abnormal lymphoid cells positive for Epstein-Barr virus encoded RNA (EBER) by in situ hybridization. b, c Inheritance modelling identified homozygous germline mutations of FAM160A1 c.2827 C > T in both affected brothers, heterozygous carriage in their mother and paternal aunt, and homozygous wildtype in their healthy older brother. d, e The non-synonymous substitution at FAM160A1 c.2827 C > T results in an amino-acid alteration from arginine to cysteine (p.R943C). Patterns and frequencies of known mutations in other cancer types are shown

Sarcoma is an uncommon and heterogeneous group of malignancies linked by their mesenchymal origin. They are rare and account for 1% of adult cancers, and 10–20% of adolescent and young adult (AYA) cancers. While there is good published literature on the incidence and distribution of sarcoma subtypes in the western populations, there is a paucity of data from Asia, particularly on the epidemiology, treatment and outcomes of STS in Asia. Formalized prospective national registries in soft tissue sarcoma (STS) are lacking and little is known about how sarcomas are treated and managed throughout the Asia-Pacific region. Due to geographical and varying affluence levels across over 50 countries, no single uniform guideline exists across Asia to inform of chemotherapeutic options. Any existent guidelines tend to be country-specific, reflecting resource availability and geographical limitation. To understand and improve STS care in Asia, one must appreciate the macroeconomics and healthcare structures in place and to work within the limitations imposed by them. Concurrently, there exists an urgency to develop strong sarcoma centres of excellence (SCE) across Asia to deliver state-of-art care to our patients. Equally important is the need to facilitate sarcoma education to patients and healthcare workers. Development of such centres is vital in improving clinical care as they provide high-quality sub-specialized care to patients within that geographical location, serve as reference centres for knowledge and education as well as nerve centres for care-coordination in a hub-and-spoke model. Key to these centres of excellence is the sarcoma multi-disciplinary team (MDT). Studies have consistently shown that patients managed in high-volume sarcoma centres, by an expert sarcoma MDT, achieve better clinical outcomes. This report serves to highlight the challenges and opportunities of sarcoma care in Asia, map out a vision for the development of SCE across Asia and highlight the areas of potential collaboration between centres to advance the science of sarcoma.

Purpose The value of screening for hepatitis B virus (HBV) infection before chemotherapy for nonhematopoietic solid tumors remains unsettled. We evaluated the cost effectiveness of universal screening before systemic therapy for sarcomas, including GI stromal tumors (GISTs). Patients and Methods Drawing from the National Cancer Centre Singapore database of 1,039 patients with sarcomas, we analyzed the clinical records of 485 patients who received systemic therapy. Using a Markov model, we compared the cost effectiveness of a screen-all versus screen-none strategy in this population. Results A total of 237 patients were screened for HBV infection. No patients developed HBV reactivation during chemotherapy. The incremental cost-effectiveness ratio per quality-adjusted life-year (QALY) of offering HBV screening to all patients with sarcomas and patients with GISTs exceeded the cost-effectiveness threshold of SG$100,000 per QALY. This result was robust in one-way sensitivity analysis. Our results show that only changes in mortality rate secondary to HBV reactivation could make the incremental cost-effectiveness ratio cross the cost-effectiveness threshold. Conclusion Universal HBV screening in patients with sarcomas or GISTs undergoing chemotherapy is not cost effective at a willingness to pay of SG$100,000 per QALY and may not be required.

Background Gastrointestinal stromal tumours (GISTs), despite complete surgical cytoreduction, are associated with recurrence rates of up to 50% at 2 years. At recurrence, tyrosine kinase inhibitor (TKI) therapy is recommended, conferring a survival of up to 55 months. Several studies have shown that patients with TKI-responsive recurrent GIST benefit from surgery. However, no studies have compared upfront surgery versus TKI alone. Methods Data were retrospectively collected from patients with recurrent GIST treated at Singapore General Hospital and National Cancer Centre Singapore over a 12-year period. Our primary end points were disease-free and overall survival (OS). Results A total of 186 patients underwent curative surgery for GIST between January 2000 and June 2012. Fifty-six (30%) patients experienced recurrence, of which 30 (54%) had resectable recurrent disease. Twenty-four patients underwent upfront surgery for their recurrence while the remaining six patients opted for non-surgical management. The median OS for all patients with recurrent GIST was 5.3 years (95% confidence interval (CI) 3.2–8.4). It was not reached for patients who underwent curative surgery for their recurrence, and was 3.9 years (95% CI 2.4–7.0) for patients who had palliative TKI and conservative management. There were significant differences in OS and disease-specific survival between patients who underwent curative surgery for recurrence compared with those who had not. Conclusion Our study shows that upfront surgery is a reasonable treatment strategy for selected patients with recurrent GIST.

To validate the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic nomogram in a single-institution cohort of patients with gastrointestinal stromal tumors (GISTs), and to compare its predictive accuracy against other established risk classification systems, including the National Institutes of Health (NIH), Armed Forces Institute of Pathology (AFIP), and Joensuu criteria. We retrospectively reviewed 289 patients who underwent surgical resection for primary localized GISTs without adjuvant imatinib therapy and compared the actuarial recurrence-free survival (RFS) with the predicted RFS. Tumors >5 cm in size, with high mitotic index, and which had ruptured were significantly associated with recurrent disease. The 2-year RFS was 77.2 % [95 % confidence interval (CI) 71.6–81.8], and the 5-year RFS was 67.9 % (95 % CI 61.7–73.4). The concordance probability of the nomogram of 2-year RFS was 0.71 (SE 0.02), and 5-year RFS was 0.71 (SE 0.19). The 2-year and 5-year MSKCC nomogram probability calculations and the AFIP criteria gave a better estimation of RFS compared to the NIH (p

Since few studies have investigated whether the Distress Thermometer (DT) in Asian adolescent and young adult (AYA) cancer patients (between 15 and 39 years), we investigated the appropriateness of the DT as a screening tool for psychological symptom burden in these AYA patients and to evaluate AYA patients’ distress across a trajectory of three time points longitudinally over a 6-month period. This was a prospective, longitudinal study. Recruited Asian AYA patients were diagnosed with lymphomas, sarcomas, primary brain malignancies, or germ cell tumors. Patients completed the DT, PedsQL Generic Core Scales, and the Rotterdam Symptom Checklist. Data were analyzed using STATA version 15. Approximately half of the patients experienced clinically significant DT distress (distress score ≥ 4) early in their cancer journey with 43.1% patients presenting with distress at time of diagnosis and 47.7% patients 1 month after diagnosis. Among AYA patients > 24 years old, worry (68.3%), insurance/financial issues (61%), treatment decisions (43.9%), work/school issues (41.5%), nervousness (41.5%), and sadness (41.5%) were the top five identified problems. On the other hand, the top five identified problems among AYA ≤ 24 years were worry (54.2%), nervousness (41.7%), bathing/dressing problems (37.5%), work/school issues (33.3%), and fatigue (33.3%). DT scores were significantly associated with certain psychological symptom burden items such as worry (p

Associations of sarcoma with inherited cancer syndromes implicate genetic predisposition in sarcoma development. However, due to the apparently sporadic nature of sarcomas, little attention has been paid to the role genetic susceptibility in sporadic sarcoma. To address this, we performed targeted-genomic sequencing to investigate the prevalence of germline mutations in known cancer-associated genes within an Asian cohort of sporadic sarcoma patients younger than 50 years old. We observed 13.6% (n = 9) amongst 66 patients harbour at least one predicted pathogenic germline mutation in 10 cancer-associated genes including ATM, BRCA2, ERCC4, FANCC, FANCE, FANCI, MSH6, POLE, SDHA and TP53. The most frequently affected genes are involved in the DNA damage repair pathway, with a germline mutation prevalence of 10.6%. Our findings suggests that genetic predisposition plays a larger role than expected in our Asian cohort of sporadic sarcoma, therefore clinicians should be aware of the possibility that young sarcoma patients may be carriers of inherited mutations in cancer genes and should be considered for genetic testing, regardless of family history. The prevalence of germline mutations in DNA damage repair genes imply that therapeutic strategies exploiting the vulnerabilities resulting from impaired DNA repair may be promising areas for translational research.

Limited data are available on how symptom burden affects health-related quality of life (HRQoL) in patients with sarcoma. This study aims to describe the symptom burden, HRQoL, and medication use in adult sarcoma patients. A single-center, cross-sectional study was conducted, and 79 patients were evaluated using three tools: the Rotterdam Symptom Checklist (RSCL), the Beck Anxiety Inventory (BAI), and the Functional Assessment of Cancer Therapy scale—General (FACT-G). Patients’ demographic and clinical information, medication history, and use of concomitant medications were recorded. The proportion of patients with clinically significant RSCL score for a particular symptom was compared with the percentage of patients receiving medication for that symptom. The mean age was 57.3 ± 15.2 years, with majority of the patients diagnosed with stromal tumor (46.8 %), leiomyosarcoma (15.2 %), and liposarcoma (10.1 %). The most prevalent physical symptoms experienced were tiredness (2.38 ± 1.00), lack of energy (2.04 ± 1.02), and difficulty sleeping (2.00 ± 1.15). The most common psychological symptoms experienced were irritability (1.92 ± 1.01), worrying (1.86 ± 0.90), and anxiety (1.68 ± 0.74). Few (6.3 %) patients received hypnotics while 33.0 % of patients reported difficulty sleeping. A proportion of patients (27.9 %) reported experiencing lack of appetite with only 1.3 % received appetite stimulants. Adult sarcoma patients experience significant physiological and psychological symptom burden, which has a strong negative impact on HRQoL, with a number of physiological symptoms undertreated with pharmacotherapy.

11047 Background: Angiosarcomas are rare, clinically-aggressive endothelial tumors with remarkable heterogeneity in terms of anatomical and etiological origins, amongst which UV-radiation and oncogenic viruses have been implicated. Methods: The genomic and transcriptomic landscapes of human angiosarcomas were examined using whole genome sequencing (n = 18) and RNAseq (n = 14). Results were validated in an extended cohort of FFPE tissue (n = 57) on various platforms. Results: We observed recurrent mutations in known angiosarcoma-associated genes including TP53, KDR, POT1 and PTPRB. The median tumor mutation burden (TMB) was 1.95 mutations per megabase and was highest in a subset of head and neck angiosarcomas (HN-AS, n = 6) harboring UV signatures. The remaining cases, including seven HN-AS, contained a significantly lower TMB (5.04 vs 0.91, p= 0.0007). In corroboration, UV exposures were validated by cyclobutane pyrimidine dimer immunohistochemistry in 15 of 35 (42.9%) HN-AS and cutaneous angiosarcomas, but not in visceral or breast angiosarcomas. Gene set enrichment analysis (GSEA) revealed upregulation of “cell cycle” and “inflammation” pathways in angiosarcomas. Notably, drug inhibition of overexpressed kinases including aurora kinase, polo-like kinase and checkpoint kinase-1 potently reduced viability in two angiosarcoma cell lines, achieving IC50s of < 1µM. Metagenomic analysis detected viral reads mapping to the human herpesvirus-7 (HHV-7) genome, which were verified by PCR and immunohistochemistry. Genomic integration of HHV-7 was demonstrated at its flanking DRR telomeric repeat sequence adjoining the subtelomeric region of chromosome 17p. Overall, HHV-7 was detected in 38 of 57 (66.7%) angiosarcomas and inversely correlated with UV exposure ( p= 0.01). GSEA and Nanostring IO360 profiling showed that “inflammation” pathways were enriched in viral-positive angiosarcomas, while “cell cycle” pathways were enriched in viral-negative cases. Compared with HHV-7 negative cases, HHV-7 positive angiosarcomas were associated with high tumor inflammation scores (TIS ≥ median 6.74) (73.3% vs 25.0%, p = 0.02). Conclusions: We identified distinct subtypes of angiosarcoma characterized by HHV7-positive “inflammation” and UV-associated “cell cycle” phenotypes.

Soft-tissue sarcomas require tailored and multidisciplinary treatment and management. However, little is known about how sarcomas are treated and managed throughout the Asia-Pacific region.MEDLINE was systematically searched using prespecified criteria. Publications (previous 10 years) that reported tumour characteristics, treatment patterns, survival outcomes, and/or safety outcomes of patients with soft-tissue sarcoma were selected. Exclusion criteria were studies of patients18 years of age; ≤ 10 patients; countries other than Australia, Hong Kong, Indonesia, Korea, Malaysia, New Zealand, Philippines, Singapore, Taiwan, or Thailand;20% benign tumours; sarcomas located in bones or joints; gastrointestinal stromal tumour; Kaposi's sarcoma; or not reporting relevant outcomes.Of the 1,822 publications retrieved, 35 (32 studies) were included. Nearly all patients (98%, 1,992/2,024; 31 studies) were treated with surgery, and more studies used adjuvant radiotherapy than chemotherapy (24 vs 17 studies). Survival outcomes and recurrence rates varied among the studies because of the different histotypes, sites, and disease stages assessed. Only 5 studies reported safety findings.These findings highlight the lack of specific data available about soft-tissue sarcomas in the Asia-Pacific region. Better efforts to understand how the sarcoma is managed and treated will help improve patient outcomes in the region.

BACKGROUND Advanced uterine leiomyosarcoma (ULMS) is an incurable disease. A significant percentage of cases of ULMS express estrogen and/or progesterone receptors (ER and/or PR). To the authors' knowledge, the role of estrogen suppression in disease management is not known. METHODS The authors performed a single-arm phase 2 study of the aromatase inhibitor letrozole at a dose of 2.5 mg daily in patients with unresectable ULMS with ER and/or PR expression confirmed by immunohistochemistry. Tumor assessments were performed at baseline, 6 weeks, 12 weeks, and every 8 weeks thereafter. Toxicity was monitored throughout treatment. The primary endpoint was the progression-free survival at 12 weeks. RESULTS A total of 27 patients was accrued, with a median of 2 prior treatment regimens (range, 0-9 treatment regimens). The median duration of protocol treatment was 2.2 months (range, 0.4 months-9.9 months). The 12-week progression-free survival rate was 50% (90% confidence interval, 30%-67%). The best response was stable disease in 14 patients (54%; 90% CI, 36%-71%). Three patients, all of whom had tumors expressing ER and PR in > 90% of tumor cells, continued to receive letrozole for > 24 weeks. The most common reason for treatment discontinuation was disease progression (85%). Letrozole was found to be well tolerated. CONCLUSIONS Letrozole met protocol-defined criteria as an agent with activity in patients with advanced ULMS. Patients with the longest progression-free survival rate were those whose tumors strongly and diffusely expressed ER and PR. Cancer 2014;120:738–743. © 2013 American Cancer Society.

Sarcomas are a rare and diverse set of cancers that disproportionately affect young people. The best possible outcome depends on access to highly specialised, multidisciplinary care. Although advances have been made in therapeutic techniques, access to some treatments might be limited by cost implications. This Review proposes an evidence-based, consensus recommendation for optimum management of bone and soft-tissue sarcoma across the Asia-Pacific region, taking into account variation in health-care resources, stratified according to the Breast Health Global Initiative resource levels. A web-based survey of 89 clinicians involved in the care of patients with sarcoma from 18 Asia-Pacific countries generated the recommendations for diagnosis, staging, and management, including supportive and palliative care, and research.