Extensive lymphadenectomy may improve survival in node negative oesophageal cancer.

Lymph node metastases are a major prognostic factor in survival of patients with oesophageal cancer. The number of lymph nodes removed during oesophagectomy has been previously proven to be associated with improved survival. The aim of this study was to examine the effect of lymph node harvest on survival specifically in pathologically node negative (pN0) patients with oesophageal cancer. Data were extracted from a prospectively populated single-surgeon database of oesophageal resections for cancer. All consecutive patients with pN0 were included. Patient-specific risk adjusted analysis of overall and disease-free survival was performed to identify the number of lymph nodes associated with improved survival. Inclusion criteria were met by 137 patients (49 squamous cell carcinoma and 88 adenocarcinoma). Adjusted for cancer stage, tumour (histological type, degree of differentiation, lympho-vascular invasion, neo-adjuvant therapy) and patient related factors (age, sex), increased lymph node number was associated with significant improvement in overall (P = 0.045) and disease free (P = 0.030) survival. Lymph node count ≥ 17 was associated with improved overall and disease-free survival. In this cohort of patients with pathologically node-negative oesophageal cancer, lymph node count of 17 or above was associated with significantly improved survival.

Does age affect oesophagectomy survival: a cohort study.

BACKGROUND: Curative oesophagectomy for oesophageal cancer is associated with considerable potential mortality. Surgeons are increasingly treating older patients presenting with oesophageal cancer as the population ages. The question remains as to the survival in an older population group, many of whom are not fit for combined multimodal therapy. This study aimed to assess the effect of age on overall survival and disease-free survival in patients undergoing curative oesophagectomy for cancer. METHODS: Patient data were analysed from a prospectively maintained database. Demographic, surgical and survival outcomes were compared between groups according to age less than 75 years or 75 and older. RESULTS: Oesophagectomy was performed in 351 patients between 1990 and 2019 (283 patients <75 years, 68 patients ≥75 years). There was a higher rate of neoadjuvant chemotherapy in the younger group (37.7% versus 7.4%; P < 0.001). The 30-day mortality between younger and older groups was similar (2.5% and 2.9%; P = 0.827). There was no statistical difference in 5-year survival rates (50.3% versus 38.6%; P = 0.082) or median survival (22.6 versus 19.3 months; P = 0.053) between groups. There was no statistical difference in 5-year disease-free survival (45.1% and 35.7%; P = 0.180). CONCLUSION: Overall survival, disease-free survival and 30-day mortality rates in patients aged 75 years and older were not statistically different to their younger counterparts. On the basis of these results, older patients should not be precluded from consideration of potentially curative oesophagectomy on age alone, providing surgery may be performed at reasonable risk.

Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating lymphocytes and improved outcome.

AIMS: Triple-negative breast cancer (TNBC) patients generally have a poor outcome; there is a pressing need to identify more effective therapeutic strategies. Clinical trials targeting programmed death 1/programmed death ligand 1 (PD1/PDL1) in melanoma and non-small-cell lung cancer have reported high response rates, and tumoral PDL1 expression has been suggested as a potential biomarker to enrich for patient response to these treatments. There are only very limited data to date reporting the expression of PDL1 in TNBC. METHODS AND RESULTS: PDL1 immunohistochemistry was performed on 161 primary TNBCs and assessed in the tumour as well as immune cells in the stromal compartment. PDL1 expression was very common in TNBC, expressed in the tumour cell membrane (64%), cytoplasm (80%) and stromal (93%) cellular compartments. Cytoplasmic tumoral expression of PDL1 was associated with a lower risk of breast cancer-specific death [hazard ratio (HR) 0.45, P = 0.035] while stromal PDL1 expression was associated with a lower rate of deaths from all causes (HR 0.305, P = 0.0042). Membranous expression of PDL1 was not associated with outcome. While both PDL1 expression and tumour-infiltrating lymphocytes were associated with a better outcome, only lymphovascular invasion and high tumour-infiltrating lymphocytes were independently prognostic for breast cancer-specific death. CONCLUSION: While PDL1 expression is frequent in TNBC, it was not independently prognostic. There were differences in outcome depending on the cellular compartment of PDL1 expression. These data provide further impetus for investigating the utility of immune checkpoint therapies in TNBC, given the clinical significance of tumour-infiltrating lymphocytes (TILs) and PDL1 expression in this cohort.

Tubular carcinoma of the breast: axillary involvement and prognostic factors.

BACKGROUND: Tubular carcinoma (TC) of the breast has a very favourable prognosis. The role for axillary staging in small TC was questioned. This study investigated the frequency of axillary metastases and prognostic factors in pure TC of the breast. It involved a retrospective review of prospectively collected data. METHODS: A consecutive series of patients presenting to The Strathfield Breast Centre (TSBC) between 1988 and 2011 were reviewed. Only pure TC was included. Information collected included demographics, surgery, pathology, adjuvant therapy and survival. RESULTS: Pure TC accounted for 146 out of 6110 cases of operable breast cancer. Ninety-five per cent were node negative (micrometastases and isolated tumour cells excluded). Ninety-eight per cent of those with known oestrogen receptor status were oestrogen receptor positive. Median tumour size was 10 mm (range 1-52 mm). Ten-year survival was 97%. Twelve per cent of patients had more than one tumour (either ipsilateral or contralateral). Eight patients had recurrent disease. All were node negative. Three of these patients died of their disease. CONCLUSION: Axillary metastases are uncommon in pure TC. Recurrent disease is not readily predicted by tumour size or node status.

Fibroblast growth factor receptor 1 (FGFR1) copy number is an independent prognostic factor in non-small cell lung cancer.

Fibroblast growth factor receptor 1 (FGFR1) is an oncogene that can potentially be targeted by tyrosine kinase inhibitors. We aimed to investigate the prevalence and prognostic significance of alterations in FGFR1 copy number in non-small cell lung cancer (NSCLC). FGFR1 status was evaluated by chromogenic silver in situ hybridisation (ISH) in tissue microarray sections from a retrospective cohort of 304 surgically resected NSCLCs and results were correlated with the clinicopathological features and overall survival. High FGFR1 gene copy number (amplification or high-level polysomy) was significantly more frequent in squamous cell carcinomas (SCC) (24.8%) and large cell carcinomas (LCC) (25%) compared to adenocarcinomas (11.3%) (p = 0.01 and p = 0.03 respectively). Among NSCLC there was no significant correlation between FGFR1-positive status and other clinicopathological features including age, gender, smoking history, tumour size, lymph node status, stage, grade, vascular, lymphatic or perineural invasion. FGFR1-positive patients showed a tendency to longer overall survival in univariate analysis (p = 0.14). Multivariate survival analysis using Cox regression model confirmed FGFR1-positive patients had a significant reduction in the risk of death compared to FGFR1-negative patients (HR 0.6; p = 0.02). High FGFR1 gene copy number is a common finding in SCC and LCC and is an independent favourable prognostic factor.

Patterns of DNA mutations and ALK rearrangement in resected node negative lung adenocarcinoma.

BACKGROUND: Many studies have examined specific mutations in patients with resected lung adenocarcinoma across heterogeneous stages, comprising predominantly advanced/metastatic disease, but there is little data regarding the mutation profile of patients with early stage node negative disease. The aim of this study was to identify patterns of mutations in early stage node negative lung adenocarcinoma. METHODS: A total of 204 patients who underwent resection for stage IB (sixth Ed American Joint Committee on Cancer) lung adenocarcinoma and received no neoadjuvant or adjuvant treatments were identified. Tumors were genotyped using the OncoCarta v1.0 kit (Sequenom, San Diego, CA) on the Sequenom MassARRAY platform. Fluorescence in situ hybridization for ALK rearrangement was also performed. RESULTS: A total of 110 (54%) patients' tumors harbored at least one mutation. KRAS, EGFR, PIK3CA, ALK, PDGFRA, AKT1, BRAF, FGFR1, and HRAS mutations were detected in tumors from 77 (37.7%), 29 (14.2%), 9 (4.4%), 2 (1%), 2 (1%), 1 (0.5%), 1 (0.5%), 1 (0.5%), and 1 (0.5%) patients respectively. Synchronous mutations (either comutations or double mutations) were identified in 18 (8.8%) patients. KRAS and PIK3CA mutations were associated with poorly differentiated tumors (p = 0.03; p = 0.02), whereas EGFR mutations were associated with well-differentiated tumors (p = 0.001). Five tumours contained EGFR mutations (one T790M and four exon 20 insertions), which are associated with resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). CONCLUSIONS: Diverse patterns of mutations are seen in resected node-negative lung adenocarcinoma including an unexpectedly low rate of ALK rearrangement, EGFR mutations associated with resistance to EGFR-TKIs and a high rate of synchronous mutations. These data may influence the design of future adjuvant targeted therapy trials.

Loss of heterozygosity of the Mutated in Colorectal Cancer gene is not associated with promoter methylation in non-small cell lung cancer.

'Mutated in Colorectal Cancer' (MCC) is emerging as a multifunctional protein that affects several cellular processes and pathways. Although the MCC gene is rarely mutated in colorectal cancer, it is frequently silenced through promoter methylation. Previous studies have reported loss of heterozygosity (LOH) of the closely linked MCC and APC loci in both colorectal and lung cancers. APC promoter methylation is a marker of poor survival in non-small cell lung cancer (NSCLC). However, MCC methylation has not been previously studied in lung cancer. Therefore, we wanted to determine if MCC is silenced through promoter methylation in lung cancer and whether this methylation is associated with LOH of the MCC locus or methylation of the APC gene. Three polymorphic markers for the APC/MCC locus were analysed for LOH in 64 NSCLC specimens and matching normal tissues. Promoter methylation of both genes was determined using methylation specific PCR in primary tumours. LOH of the three markers was found in 41-49% of the specimens. LOH within the MCC locus was less common in adenocarcinoma (ADC) (29%) than in squamous cell carcinoma (SCC) (72%; P=0.006) or large cell carcinoma (LCC) (75%; P=0.014). However, this LOH was not accompanied by MCC promoter methylation, which was found in only two cancers (3%). In contrast, 39% of the specimens showed APC methylation, which was more common in ADC (58%) than in SCC (13%). Western blotting revealed that MCC was expressed in a subset of lung tissue specimens but there was marked variation between patients rather than between cancer and matching non-cancer tissue specimens. In conclusion, we have shown that promoter methylation of the APC gene does not extend to the neighbouring MCC gene in lung cancer, but LOH is found at both loci. The variable levels of MCC expression were not associated with promoter methylation and may be regulated through other cellular mechanisms.

Surgical management of melanoma lung metastasis: an analysis of survival outcomes in 292 consecutive patients.

BACKGROUND: The role of surgical resection of melanoma lung metastases (MLM) remains controversial. Some authorities advocate an aggressive surgical approach, while others recommend a conservative strategy. This study sought to identify the clinicopathologic and predictors of outcome after surgical management of MLM in a large series of melanoma patients from a single institution. METHODS: All patients undergoing surgical management of MLM between November 1984 and April 2010 were identified and predictors of outcome analyzed. RESULTS: Of the 292 patients eligible for the study, 112 (38%) had previously undergone surgery for nonpulmonary recurrences. Four patients (1%) died within 30 days of surgery for MLM. The median progression-free survival time was 10 months. The median overall survival and 3- and 5-year survival were 23 months [95% confidence interval (CI) 17­30], 41 and 34%, respectively. Metastasis size >2 cm [hazard ratio (HR) 1.4, 95% CI 1.0­1.8, P = 0.03, HR 1.6, 95% CI 1.2­2.2; P = 0.002] and positive surgical margin (HR 1.5, 95% CI 1.2­1.9, P < 0.001; HR 1.4, 95% CI 1.1­1.7, P = 0.003) were independently associated with poorer progression-free survival and overall survival, respectively. The presence of more than one metastasis (HR 1.4, 95% CI 1.1­1.7, P = 0.013) was independently associated with poorer overall survival. CONCLUSIONS: The results support the role of pulmonary metastasectomy in selected patients with MLM. Patients with small (<2 cm) and solitary tumors that can be completely resected with a negative margin are most likely to experience prolonged survival.

Loss of special AT-rich binding protein 1 expression is a marker of poor survival in lung cancer.

INTRODUCTION: Lung cancer is the leading cause of cancer-related mortality and requires more effective molecular markers of prognosis and therapeutic responsiveness. Special AT-rich binding protein 1 (SATB1) is a global genome organizer that recruits chromatin remodeling proteins to epigenetically regulate hundreds of genes in a tissue-specific manner. Initial studies suggest that SATB1 overexpression is a predictor of poor prognosis in breast cancer, but the prognostic significance of SATB1 expression has not been evaluated in lung cancer. METHODS: A cohort of 257 lung cancers was evaluated by immunohistochemistry. Epigenetic silencing of SATB1 was examined in cell lines by 5-Aza 2-deoxycytidine and trichostatin A treatment, and chromatin immunoprecipitation. RESULTS: Significant loss of SATB1 expression was found in squamous preinvasive lesions (p < 0.04) and in non-small cell lung cancers (p < 0.001) compared with matched normal bronchial epithelium. Loss of SATB1 independently predicted poor cancer-specific survival in squamous cell carcinomas (SCCs; hazard ratio: 2.06, 95% confidence interval: 1.2-3.7, p = 0.016). Treatment of lung cancer cell lines with the histone deacetylase inhibitor trichostatin A resulted in up-regulation of SATB1. SATB1 was associated with a decrease in the active chromatin mark acetylated histone H3K9 and an increase in the repressive polycomb mark trimethylated H3K27 in a SCC cell line relative to a normal bronchial epithelial cell line. CONCLUSIONS: This is the first study showing that SATB1 expression is lost in early preinvasive squamous lesions and that loss of SATB1 is associated with poor prognosis in lung SCC. We hypothesize that the SATB1 gene is epigenetically silenced through histone modifications.

Ratio of metastatic lymph nodes to total number of nodes resected is prognostic for survival in esophageal carcinoma.

INTRODUCTION: The role of the number of metastatic nodes in esophageal cancer surgery is of interest. We assess predictors of survival after oesophagectomy for esophageal and gastroesophageal junction malignancy. METHODS: Prospective data of consecutive patients undergoing oesophagectomy and systematic lymphadenectomy between 1991 and 2007. RESULTS: Of 224 patients, 148 patients (66%) had adenocarcinoma, 70 (31%) squamous cell carcinoma, and 6 (2.6%) were other tumor types. Five-year survival was 43% with hospital mortality of 3.5%. Locoregional recurrence occurred in 14%. The total number of affected nodes significantly reduced survival (four or more metastatic nodes). Further analysis of the ratio of nodes affected to the total number resected showed a significant decrease in survival as the percentage of positive nodes increased (p < 0.001). CONCLUSIONS: Patients undergoing surgery for esophageal cancer should be staged according to a minimum total number of metastatic lymph nodes and ratios because this more accurately predicts survival than current staging systems.