Post-Treatment Neutrophil and Lymphocyte Counts Predict Progression-Free Survival Following First-Line Chemotherapy in Hodgkin's Lymphoma.

Hodgkin's lymphoma carries an excellent prognosis with modern chemotherapy, but a significant proportion of patients remain refractory to or relapse after first-line treatment. Immunological changes post-treatment, such as chemotherapy-induced neutropenia (CIN) or lymphopenia, have shown prognostic significance in multiple tumor types. Our study aims to investigate the prognostic value of immunologic changes in Hodgkin's lymphoma by examining the post-treatment lymphocyte count (pALC), neutrophil count (pANC) and the neutrophil-lymphocyte ratio (pNLR). Patients treated for classical Hodgkin's lymphoma at the National Cancer Centre Singapore using ABVD-based regimens were retrospectively analyzed. An optimal cut-off value for high pANC, low pALC and high pNLR in predicting progression-free survival was determined by receiver operating curve analysis. Survival analysis was performed using the Kaplan-Meier method and multivariable Cox proportional models. Overall OS and PFS were excellent, with a 5-year OS of 99.2% and a 5-year PFS of 88.2%. Poorer PFS was associated with high pANC (HR 2.99, p = 0.0392), low pALC (HR 3.95, p = 0.0038) and high pNLR (p = 0.0078). In conclusion, high pANC, low pALC and high pNLR confer a poorer prognosis for Hodgkin's lymphoma. Future studies should evaluate the potential of improving treatment outcomes by the adjustment of chemotherapy dose intensity based on post-treatment blood counts.

Multiregion sequencing of sarcomatoid renal cell carcinoma arising from autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited cystic kidney disease associated with a spectrum of various renal and extrarenal manifestations, including increased risk of kidney cancers. Here, we present the initial molecular description of sarcomatoid renal cell carcinoma (sRCC) arising in the setting of ADPKD. METHODS: Multiregion whole-exome sequencing and whole transcriptomic sequencing were used to examine intratumoral molecular heterogeneity among histologically-distinct spindle (sarcomatoid), epithelioid, or biphasic compartments within the tumor and compared with the non-malignant ADPKD component. RESULTS: Spindle and biphasic components harbored several overlapping driver gene mutations, but do not share any with the epithelioid component. Mutations in ATM, CTNNB1, and NF2 were present only in the biphasic and spindle components, while mutations in BID, FLT3, ARID1B, and SMARCA2 were present only in the epithelioid component. We observed dichotomous evolutionary pathways in the development of epithelioid and spindle compartments, involving early mutations in TP53 and ATM/CTNNB1/NF2 respectively. Wnt, PI3K-mTOR, and MAPK signaling pathways, known key mechanisms involved in ADPKD development, featured prominently in the sarcomatoid component. CONCLUSION: This highlights that common pro-oncogenic signals are present between ADPKD and sRCC providing insights into their shared pathobiology.

Towards precision oncology in angiosarcomas using next generation "omic" technologies.

Angiosarcomas are a group of aggressive tumors of vascular origin. Although thought to be a rare cancer constituting just 1-2% of all soft tissue sarcomas, recent observations suggest that angiosarcomas are more common amongst Asian populations as compared to the West, suggesting the possibility of distinct genetic or environmental triggers influencing its pathogenesis. Advances in genomic sequencing efforts have led to the discovery of ultraviolet mutation signatures and high tumor mutation burden as common features of angiosarcoma of the head and neck. In addition, multi-omic analyses integrated with clinical data identified 3 subtypes characterized by distinctive etiological and biological phenotypes, with potential implications on precision therapy. The systemic and local immune milieu, as well as the presence of "giant" tumor cells, was also recently demonstrated to influence clinical behavior and patient outcomes, further highlighting complexities of this disease. Improvements in next generation "omic"-based technologies are expected to improve our understanding of angiosarcoma and guide the development of precision oncology in this rare cancer.

Clinical implications of systemic and local immune responses in human angiosarcoma.

Angiosarcomas are a rare subtype of soft-tissue sarcomas which exhibit aggressive clinical phenotypes with limited treatment options and poor outcomes. In this study, we investigated the clinical relevance of the peripheral blood neutrophil-to-lymphocyte ratio (NLR) as a marker of systemic immune response, as well as its correlation with intra-tumoral immune profiles in a subgroup of cases (n = 35) using the NanoString PanCancer IO360 panel and multiplex immunohistochemistry. In the overall cohort (n = 150), angiosarcomas of the head and neck (AS-HN) comprised most cases (58.7%) and median overall survival (OS) was 1.1 year. NLR, classified as high in 78 of 112 (70%) evaluable patients, was independently correlated with worse OS (HR 1.84, 95%CI 1.18-2.87, p = 0.0073). Peripheral blood NLR was positively correlated with intra-tumoral NLR (tNLR) (Spearman's rho 0.450, p = 0.0067). Visualization of tumor-infiltrating immune cells confirmed that tNLR scores correlated directly with both neutrophil (CD15+ cells, rho 0.398, p = 0.0198) and macrophage (CD68+ cells, rho 0.515, p = 0.0018) cell counts. Interestingly, tNLR correlated positively with oncogenic pathway scores including angiogenesis, matrix remodeling and metastasis, and cytokine and chemokine signaling, as well as myeloid compartment scores (all p < 0.001). In patients with documented response assessment to first-line chemotherapy, these pathway scores were all significantly higher in non-responders (47%) compared to responders. In conclusion, systemic and local immune responses may inform chemotherapy response and clinical outcomes in angiosarcomas.

Intentional Poisoning in Pediatric Patients: Examining the Risk Factors.

OBJECTIVES: Poisonings in children are common reasons for presentation to the emergency department and can potentially have serious complications. Our research aims to review risk factors leading to intentional self-poisoning. METHODS: A retrospective medical record review of all intentional pediatric poisoning cases presenting to the Children's Emergency at National University Hospital, Singapore between January 2014 and December 2015 was performed. RESULTS: Eighty-seven cases of intentional poisonings were identified, 31 (36.5%) of which were with suicidal intent. The majority of cases were female (85.1%) and adolescents older than 16 years (93.1%). A known psychiatric history was present in 57.5% and 62 (71.3%) had a history of deliberate self-harm. Being diagnosed with a new psychiatric illness during that presentation was associated with a history of self-harm (adjusted odds ratio [Adj OR], 6.74; 95% confidence interval [CI]; 1.04-43.62; P = 0.045). Twenty-seven (31.0%) patients had a history of intentional poisoning, and 15 (17.2%) went on to have subsequent presentations for poisoning. Recurrent poisoning attempts were strongly associated with a known psychiatric history (Adj OR, 5.91; 95% CI, 1.62-21.58; P = 0.007) and a history of deliberate self-harm (Adj OR, 7.49; 95% CI, 1.38-40.66; P = 0.02). Deliberate overdosing on personal long-term medication was seen in 15 (35.7%) of 42, of which 12 (80%) of 15 were psychiatric medications. CONCLUSIONS: Known psychiatric history or a history of deliberate self-harm are risk factors for intentional poisoning. Appropriate risk stratification and preemptive interventions involving closer surveillance or cognitive behavioral programs are possible measures to prevent intentional self-poisoning, especially in these at-risk groups.

Bizarre giant cells in human angiosarcoma exhibit chemoresistance and contribute to poor survival outcomes.

Giant cells (GC) are a poorly understood subset of tumor cells that have been increasingly recognized as a potential contributor to tumor heterogeneity and treatment resistance. We aimed to characterize the biological and clinical significance of GC in angiosarcoma, an aggressive rare cancer of endothelial origin. Archival angiosarcoma samples were examined for the presence of GC and compared with clinicopathological as well as NanoString gene expression data. GC were examined in angiosarcoma cell lines MOLAS and ISOHAS using conventional and electron microscopy, single cell whole genome profiling, and other assays. In the cell lines, GC represented a rare population of mitotically active, non-senescent CD31+ cells, and shared similar genomic profiles with regular-sized cells, consistent with a malignant endothelial phenotype. GC remained viable and persisted in culture following exposure to paclitaxel and doxorubicin. In patient samples, GC were present in 24 of 58 (41.4%) cases. GC was correlated with poorer responses to chemotherapy (25.0% vs 73.3%, P = 0.0213) and independently contributed to worse overall survival outcomes (hazard ratio 2.20, 95% confidence interval 1.17-4.15, P = 0.0142). NanoString profiling revealed overexpression of genes, including COL11A1, STC1, and ERO1A, accompanied by upregulation of immune-related metabolic stress and metastasis/matrix remodeling pathways in GC-containing tumors. In conclusion, GC may contribute to chemoresistance and poor prognosis in angiosarcoma.

Clinical Features of Plasmablastic Lymphoma: Case Series From an Asian Tertiary Cancer Center and Literature Review.

BACKGROUND: Plasmablastic lymphoma (PBL) is an aggressive subtype of mature B-cell non-Hodgkin lymphoma. Given its rarity, there remains a lack of clinicopathological data to guide its management, particularly on Asian patients. METHODS: We conducted a retrospective chart review of 10 patients diagnosed with PBL at the National Cancer Centre Singapore and performed a literature review of similar studies on Asian cohorts. RESULTS: Most patients were male (n = 9), with median age at diagnosis of 55 years (range, 33 - 91 years). Seven (70%) patients were considered to be immunocompromised. In the overall cohort, the median overall survival (OS) was 19.4 months with 5-year survival estimates given at 60% and 36% for OS and progression-free survival (PFS), respectively. At diagnosis, patients with HIV/AIDS (n = 5) were younger compared to others (median, 43 vs. 61 years; P = 0.0278), had greater number of nodal site involvement (median, 6 vs. 0; P = 0.0333), and higher international prognostic index (IPI) scores (P = 0.034 for trend). Amongst different chemotherapy used, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (EPOCH)-based regimens (n = 6) elicited prominent complete response rates (83%) and led to durable responses even in the setting of advanced stage, high-risk IPI score and immunodeficiency. CONCLUSIONS: In conclusion, our study describes the features of PBL in an Asian cohort and highlights disease features unique to HIV-associated PBL.

Biological significance and prognostic relevance of peripheral blood neutrophil-to-lymphocyte ratio in soft tissue sarcoma.

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 < 0.0001). Progression of localized disease at diagnosis to metastatic relapse within the same patients was associated with an interval increase in NLR (median: 3.21 vs 3.74, 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.