Treatment and long term safety outcomes of Peptide Receptor Radionuclide Therapy for metastatic neuroendocrine tumours: an Asian experience.

Peptide-receptor radionuclide therapy (PRRT) is a targeted molecular therapy used to treat neuroendocrine tumours (NET). It has been shown to be effective and well-tolerated in patients with metastatic neuroendocrine tumours in several centres in United States (US), Europe and Australia. Tolerability and efficacy data emerging from Asian centres remain few. Epidemiological evidence suggests that there are differences in neuroendocrine neoplasms between the population groups. We aim to describe the treatment and safety outcomes of PRRT in the Asian population. Methods One hundred and seven (107) patients with metastatic neuroendocrine tumour who had undergone PRRT treatment from January 2012 to March 2019 were included in this retrospective study. The response rates using RECIST1.1 and qualitative analysis were examined. The overall and progression free survival curves were also evaluated. Results The median progression free survival was 49 months. Response assessment after completion of treatment showed that 33(37.9%) of 87 patients had partial or complete response. Subgroup analysis comparing high- and low-grade NET showed that there was a significant difference in the time to progression curves. Comparison of the number of cycles and progression free and overall survival also showed a significant difference. Ten patients (9%) had grade 3 or more haematological toxicities. Four patients (4%) had grade 3/4 hepatobiliary toxicities, although the presence of extensive liver metastases was a confounding factor. None of the patients had grade 3/4 acute kidney injury. Conclusion Our results show that PRRT is safe and effective in the treatment of metastatic neuroendocrine tumour in the Asian population. There was a significant difference in the progression free survival curves between low-grade and high-grade NET, and in the progression free and overall survival comparing the number of cycles received.

Pairing a prognostic target with potential therapeutic strategy for head and neck cancer.

OBJECTIVES: We have previously identified and validated a panel of molecular prognostic markers (ATP13A3, SSR3, and ANO1) for Head and Neck Squamous Cell Carcinoma (HNSCC). The aim of this study was to investigate the consequence of ATP13A3 dysregulation on signaling pathways, to aid in formulating a therapeutic strategy targeting ATP13A3-overexpressing HNSCC. MATERIALS AND METHODS: Gene Set Enrichment Analysis (GSEA) was performed on HNSCC microarray expression data (Internal local dataset [n = 92], TCGA [n = 232], EMBL [n = 81]) to identify pathways associated with high expression of ATP13A3. Validation was performed using immunohistochemistry (IHC) on tissue microarrays (TMAs) of head and neck cancers (n = 333), staining for ATP13A3 and phosphorylated Aurora kinase A (phospho-T288). Short interfering RNA was used to knockdown ATP13A3 expression in patient derived HNSCC cell lines. Protein expression of ATP13A3 and Aurora kinase A was then assessed by immunoblotting. RESULTS: GSEA identified Aurora kinase pathway to be associated with high expression of ATP13A3 (p = 0.026). The Aurora kinase pathway was also associated with a trend towards poor prognosis and tumor aggressiveness (p = 0.086, 0.094, respectively). Furthermore, the immunohistochemical staining results revealed a significant association between Aurora kinase activity and high ATP13A3 expression (p < 0.001). Knockdown of ATP13A3 in human head and neck cell lines showed decrease in Aurora kinase A levels. CONCLUSION: Tumors with high ATP13A3 are associated with high Aurora kinase activity. This suggests a potential therapeutic role of Aurora kinase inhibitors in a subset of poor prognosis HNSCC patients with overexpression of ATP13A3.

Germline Polymorphisms and Length of Survival of Nasopharyngeal Carcinoma: An Exome-Wide Association Study in Multiple Cohorts.

Germline polymorphisms are linked with differential survival outcomes in cancers but are not well studied in nasopharyngeal carcinoma (NPC). Here, a two-phase association study is conducted to discover germline polymorphisms that are associated with the prognosis of NPC. The discovery phase includes two consecutive hospital cohorts of patients with NPC from Southern China. Exome-wide genotypes at 246 173 single nucleotide polymorphisms (SNPs) are determined, followed by survival analysis for each SNP under Cox proportional hazard regression model. Candidate SNP is replicated in another two independent cohorts from Southern China and Singapore. Meta-analysis of all samples (n = 5553) confirms that the presence of rs1131636-T, located in the 3'-UTR of RPA1, confers an inferior overall survival (HR = 1.33, 95% CI = 1.20-1.47, P = 6.31 × 10-8). Bioinformatics and biological assays show that rs1131636 has regulatory effects on upstream RPA1. Functional studies further demonstrate that RPA1 promotes the growth, invasion, migration, and radioresistance of NPC cells. Additionally, miR-1253 is identified as a suppressor for RPA1 expression, likely through regulation of its binding affinity to rs1131636 locus. Collectively, these findings provide a promising biomarker aiding in stratifying patients with poor survival, as well as a potential drug target for NPC.

Impact of Radiotherapy on Neck Dissection Nodal Count in Patients With Head and Neck Cancer.

OBJECTIVES/HYPOTHESIS: Our study aimed to review the impact of preoperative radiotherapy (RT) and other factors on the lymph node count of neck dissection (ND) specimens from patients with head and neck cancer (HNC). A retrospective study was conducted on all patients with head and neck cancers who had undergone NDs in Singapore General Hospital between 1992 and 2013. STUDY DESIGN: Retrospective study. METHODS: Patients were categorized into two groups: patients treated with RT with or without chemotherapy before ND and patients who had undergone ND surgery without previous history of RT. The primary endpoint for this study would be the lymph node count from ND. RESULTS: The study cohort consists of 1,024 NDs on 829 patients. There were 597 (58.3%) radical/modified radical NDs involving levels I-V. Within this group, 75 (12.6%) NDs had preoperative RT. Preoperative RT and age were found to significantly reduce nodal yield in both univariate and multivariate analysis in the radical/modified radical ND subgroup. In our multivariate analysis, preoperative RT was shown to decrease the nodal yield by 7.464 (P = .0002, 95% confidence interval [CI]: -11.35 to -3.58). Advanced age independently decreases nodal yield, even after accounting for the effect of RT (P = .0002, 95% CI: -0.27 to -0.08). In addition, preoperative RT has a more pronounced effect in reducing lymph node count in the older age group. CONCLUSIONS: Preoperative RT and advanced age are independent and synergistic factors that reduce nodal count from NDs in patients with head and neck cancers. LEVEL OF EVIDENCE: 4 Laryngoscope, 130: 1947-1953, 2020.

A three gene immunohistochemical panel serves as an adjunct to clinical staging of patients with head and neck cancer.

BACKGROUND: Current management of head and neck squamous cell carcinoma (HNSCC) depends on tumor staging. Despite refinements in clinical staging algorithms, outcomes remain unchanged for the last two decades. In this study, we set out to identify a small, clinically applicable molecular panel to aid prognostication of patients with HNSCC. MATERIALS AND METHODS: Data from The Cancer Genome Atlas (TCGA) was used to derive copy number aberrations and expression changes to identify putative prognostic genes. To account for cross entity relevance of the biomarkers, HNSCC (n = 276), breast (n = 808) and lung cancer (n = 282) datasets were used to identify robust and reproducible markers with prognostic potential. Validation was performed using immunohistochemistry (IHC) on tissue microarrays of an independent cohort of HNSCC (n = 333). FINDINGS: Using GISTIC algorithm together with gene expression analysis, we identified six putative prognostic genes in at least two out of three cancers analyzed, of which four were successfully optimized for automated IHC. Of these, three were successfully validated; each molecular target being significantly prognostic on univariate analysis. Patients were differentially segregated into four prognostic groups based on the number of genes dysregulated (p < 0.001). The IHC panel remained an independent predictor of survival after adjusting for known survival covariates including clinical staging criteria in a multivariate Cox regression model (p < 0.001). . INTERPRETATION: We have identified and validated a clinically applicable IHC biomarker panel that is independently associated with overall survival. This panel is readily applicable, serving as a useful adjunct to current staging systems and provides novel targets for future therapeutic strategies.

Phenotype-driven precision oncology as a guide for clinical decisions one patient at a time.

Genomics-driven cancer therapeutics has gained prominence in personalized cancer treatment. However, its utility in indications lacking biomarker-driven treatment strategies remains limited. Here we present a "phenotype-driven precision-oncology" approach, based on the notion that biological response to perturbations, chemical or genetic, in ex vivo patient-individualized models can serve as predictive biomarkers for therapeutic response in the clinic. We generated a library of "screenable" patient-derived primary cultures (PDCs) for head and neck squamous cell carcinomas that reproducibly predicted treatment response in matched patient-derived-xenograft models. Importantly, PDCs could guide clinical practice and predict tumour progression in two n = 1 co-clinical trials. Comprehensive "-omics" interrogation of PDCs derived from one of these models revealed YAP1 as a putative biomarker for treatment response and survival in ~24% of oral squamous cell carcinoma. We envision that scaling of the proposed PDC approach could uncover biomarkers for therapeutic stratification and guide real-time therapeutic decisions in the future.Treatment response in patient-derived models may serve as a biomarker for response in the clinic. Here, the authors use paired patient-derived mouse xenografts and patient-derived primary culture models from head and neck squamous cell carcinomas, including metastasis, as models for high-throughput screening of anti-cancer drugs.

Validation and comparison between current prognostication systems for pancreatic neuroendocrine neoplasms: A single-institution experience with 176 patients.

BACKGROUND: This article aims to validate and compare the performance of 6 prognostication systems-the World Health Organization 2010 grading criteria, the European Neuroendocrine Tumour Society and the American Joint Committee for Cancer staging systems, the Memorial Sloan Kettering Cancer Center staging and grading systems, as well as the Bilimoria criteria in a cohort of patients with pancreatic neuroendocrine neoplasms at a single institution. METHODS: A retrospective review of 176 patients with histologically proven pancreatic neuroendocrine neoplasm was performed. The prognostic ability of the various prognostication systems for pancreatic neuroendocrine neoplasm was assessed by analyzing the homogeneity, discriminatory ability, monotonicity of gradient, and Akaike information criteria. RESULTS: The 5-year overall survival for the 176 patients was 69% and 5-year recurrence-free survival in 119 patients who underwent curative resection was 78%. Comparison between the 6 prognostication systems demonstrated that the World Health Organization 2010 system had the lowest Akaike information criteria score and was hence the best prognostication system in predicting overall survival and recurrence-free survival rates in our cohort of patients. The European Neuroendocrine Tumour Society was superior to the American Joint Committee for Cancer in prognosticating overall survival rates for pancreatic neuroendocrine neoplasms, as there was a statistically significant difference in overall survival across the different stages when stratified by the European Neuroendocrine Tumour Society, while the use of the American Joint Committee for Cancer was limited to distinguishing between patients in stages I and II versus stages III and IV only. CONCLUSION: All 6 prognostication systems were useful in the prognostication of pancreatic neuroendocrine neoplasm. The World Health Organization 2010 grading system was the best prognostication system in predicting both overall survival in our entire cohort of patients and recurrence-free survival in the subset of patients who underwent curative resection.

A new prognostic histopathologic classification of nasopharyngeal carcinoma.

BACKGROUND: The current World Health Organization (WHO) classification of nasopharyngeal carcinoma (NPC) conveys little prognostic information. This study aimed to propose an NPC histopathologic classification that can potentially be used to predict prognosis and treatment response. METHODS: We initially developed a histopathologic classification based on the morphologic traits and cell differentiation of tumors of 2716 NPC patients who were identified at Sun Yat-sen University Cancer Center (SYSUCC) (training cohort). Then, the proposed classification was applied to 1702 patients (retrospective validation cohort) from hospitals outside SYSUCC and 1613 patients (prospective validation cohort) from SYSUCC. The efficacy of radiochemotherapy and radiotherapy modalities was compared between the proposed subtypes. We used Cox proportional hazards models to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for overall survival (OS). RESULTS: The 5-year OS rates for all NPC patients who were diagnosed with epithelial carcinoma (EC; 3708 patients), mixed sarcomatoid-epithelial carcinoma (MSEC; 1247 patients), sarcomatoid carcinoma (SC; 823 patients), and squamous cell carcinoma (SCC; 253 patients) were 79.4%, 70.5%, 59.6%, and 42.6%, respectively (P < 0.001). In multivariate models, patients with MSEC had a shorter OS than patients with EC (HR = 1.44, 95% CI = 1.27-1.62), SC (HR = 2.00, 95% CI = 1.76-2.28), or SCC (HR = 4.23, 95% CI = 3.34-5.38). Radiochemotherapy significantly improved survival compared with radiotherapy alone for patients with EC (HR = 0.67, 95% CI = 0.56-0.80), MSEC (HR = 0.58, 95% CI = 0.49-0.75), and possibly for those with SCC (HR = 0.63; 95% CI = 0.40-0.98), but not for patients with SC (HR = 0.97, 95% CI = 0.74-1.28). CONCLUSIONS: The proposed classification offers more information for the prediction of NPC prognosis compared with the WHO classification and might be a valuable tool to guide treatment decisions for subtypes that are associated with a poor prognosis.

Eight-signature classifier for prediction of nasopharyngeal [corrected] carcinoma survival.

PURPOSE: Currently, nasopharyngeal carcinoma (NPC) prognosis evaluation is based primarily on the TNM staging system. This study aims to identify prognostic markers for NPC. PATIENTS AND METHODS: We detected expression of 18 biomarkers by immunohistochemistry in NPC tumors from 209 patients and evaluated the association between gene expression level and disease-specific survival (DSS). We used support vector machine (SVM)--based methods to develop a prognostic classifier for NPC (NPC-SVM classifier). Further validation of the NPC-SVM classifier was performed in an independent cohort of 1,059 patients. RESULTS: The NPC-SVM classifier integrated patient sex and the protein expression level of seven genes, including Epstein-Barr virus latency membrane protein 1, CD147, caveolin-1, phospho-P70S6 kinase, matrix metalloproteinase 11, survivin, and secreted protein acidic and rich in cysteine. The NPC-SVM classifier distinguished patients with NPC into low- and high-risk groups with significant differences in 5-year DSS in the evaluated patients (87% v 37.7%; P < .001) in the validation cohort. In multivariate analysis adjusted for age, TNM stage, and histologic subtype, the NPC-SVM classifier was an independent predictor of 5-year DSS in the evaluated patients (hazard ratio, 4.9; 95% CI, 3.0 to 7.9) in the validation cohort. CONCLUSION: As a powerful predictor of 5-year DSS among patients with NPC, the newly developed NPC-SVM classifier based on tumor-associated biomarkers will facilitate patient counseling and individualize management of patients with NPC.

Fine needle aspiration cytology of breast cancer in women aged 70 years and older.

AIMS: Elderly breast cancers are associated with a more favourable biological marker profile and higher proportion of specific subtypes, some of which are of low histological grade. We reviewed the fine needle aspiration cytology (FNAC) to assess the cytological characteristics and any clues to assist in the diagnosis. METHODS: The aspirates of 140 cancers of various histological types and grades and 39 benign lesions were evaluated for 13 cytological parameters including cellularity of the direct and cytospin smears, epithelial cell clusters, cellular atypism, cytoplasmic features, vacuoles, mitotic figures, presence of myoepithelial cells, single background epithelial cells, the presence of naked nuclei, stromal fragments and necrosis. RESULTS: We found that the presence of background single epithelial cells, atypism of such cells, absence of benign appearing epithelial fragments, nuclear atypism of the epithelial cells within the fragments, presence of moderate amount of cytoplasm of these cells, absence of myoepithelial cells within the cluster, and absence of bipolar nuclei in the background have a strong association with malignancy. Scoring only the presence of single cells in the background, single cell atypism and the absence of bipolar nuclei in a scoring system can differentiate between benign and malignant aspirates with high (>90%) sensitivity and specificity. CONCLUSIONS: Assessing the presence of single cells in the background, single cell atypism and the absence of bipolar nuclei facilitates identification of malignancy in the aspiration of breast lesions from elderly patients.

Fine needle aspiration cytology in young women with breast cancer: diagnostic difficulties.

BACKGROUND: Breast carcinoma is the most common malignancy in women worldwide. Though fine needle aspiration cytology (FNAC) plays an important role in preoperative diagnosis, there may be diagnostic delays in affected young women due to a lower index of suspicion. METHODS: The files of the Departments of Pathology, Singapore General Hospital, Singapore, and Prince of Wales Hospital, Hong Kong, were searched for cases of breast carcinoma in women aged 35 years or less. Those with prior FNA procedures comprised our study group. The FNA smears were reviewed and classified into five categories: inadequate, benign, equivocal, suspicious, malignant. The findings were correlated with subsequent histology. RESULTS: Thirty-four women aged 35 years and below underwent 35 FNACs, with one woman having bilateral FNA procedures. Upon review, one (2.9%) was classified as inadequate, one (2.9%) benign, five (14.3%) equivocal, five (14.3%) suspicious, 21 (60%) malignant and slides were not available for review for two (5.6%) cases. For six benign and equivocal cytological diagnoses, subsequent histology disclosed pure ductal carcinoma in situ (DCIS, 1 case), mucocoele-like lesions with DCIS (2 cases), invasive and in situ ductal carcinoma with neuroendocrine features (1 case) and two cases of invasive ductal carcinoma. CONCLUSION: Diagnostic difficulties in cytological interpretation of aspirates from breast carcinoma in young women may lead to unwanted delays, which occurred in six (17.6%) of 34 women in our series. Low grade cancers posing a pitfall in cytological diagnosis have to be considered.