Promoter hypomethylation of NY-ESO-1, association with clinicopathological features and PD-L1 expression in non-small cell lung cancer.

Cancer-Testis antigens (CTA) are immunogenic molecules with normal tissue expression restricted to testes but with aberrant expression in up to 30% of non-small cell lung cancers (NSCLCs). Regulation of CTA expression is mediated in part through promoter DNA methylation. Recently, immunotherapy has altered treatment paradigms in NSCLC. Given its immunogenicity and ability to be re-expressed through demethylation, NY-ESO-1 promoter methylation, protein expression and its association with programmed death receptor ligand-1 (PD-L1) expression and clinicopathological features were investigated. Lung cancer cell line demethylation resulting from 5-Aza-2'-deoxycytidine treatment was associated with both NY-ESO-1 and PD-L1 re-expression in vitro but not increased chemosensitivity. NY-ESO-1 hypomethylation was observed in 15/94 (16%) of patient samples and associated with positive protein expression (P < 0.0001). In contrast, PD-L1 expression was observed in 50/91 (55%) but strong expression in only 12/91 (13%) cases. There was no association between NY-ESO-1 and PD-L1 expression, despite resultant re-expression of both by 5-Aza-2'-deoxycytidine. Importantly, NY-ESO-1 hypomethylation was found to be an independent marker of poor prognosis in patients not treated with chemotherapy (HR 3.59, P = 0.003) in multivariate analysis. In patients treated with chemotherapy there were no differences in survival associated with NY-ESO-1 hypomethylation. Collectively, these results provided supporting evidence for the potential use of NY-ESO-1 hypomethylation as a prognostic biomarker in stage 3 NSCLCs. In addition, these data highlight the potential to incorporate demethylating agents to enhance immune activation, in tumours currently devoid of immune infiltrates and expression of immune checkpoint genes.

Lymphadenectomy with radical cystectomy at an Australian tertiary referral institution: time trends and impact on oncological outcomes.

BACKGROUND: Lymph node dissection (LND) with radical cystectomy (RC) for surgical treatment of invasive urothelial carcinoma of the bladder can improve staging and has possible therapeutic benefit. The aim of this study was to assess utilization and extent of LND with RC at our institution and determine its impact on oncological outcomes. METHODS: Using surgical databases and hospital coding, clinical and histopathological characteristics of 87 patients who underwent RC at Austin Health between 2004 and 2011 were retrospectively analysed. Associations of predictor variables with LND use and lymph node (LN) status were analysed using logistic regression. Survival analyses were undertaken using Cox proportional hazard models. RESULTS: Fifty-eight (65.9%) patients underwent LND, with a clear trend over time in the proportion of patients undergoing LND (three of seven in 2004 up to 10 of 10 in 2011, P < 0.001) and the median (range) of LN yield from five (2-19) in 2004 to 18 (7-35) in 2011 (P < 0.001). Year of treatment was the only significant predictor (univariately and multivariately) of a patient undergoing LND. Multivariately, a significant association with nodal metastases was found for cN stage and planned extent of LND preoperatively, and pT stage postoperatively. LN status was associated significantly with recurrence-free survival with best outcomes in patients who were node-negative on a pelvic LND. A similar trend was seen for cancer-specific survival (P = 0.053). CONCLUSIONS: Over the study period, there was an increase in the use of pelvic LND and LN numbers retrieved during RC. LN status appears to impact on recurrence-free survival, and possibly cancer-specific survival.

Mistaken identity: granular cell astrocytoma masquerading as histiocytosis of the central nervous system.

Granular cell astrocytoma (GCA) is an uncommon malignant glial tumour that is associated with a poor prognosis. GCA cells have some morphological and immunohistochemical similarities to macrophages. In this case, a small biopsy contained no typical astrocytoma and large rounded lesional cells were interpreted as negative for glial fibrillary acidic protein and S100 and positive for CD68, a commonly used marker for macrophages. A diagnosis of a histiocytosis was made. When the patient failed to respond to first and second line therapy, tumour resection was undertaken and the pathology then showed typical morphologic and immunohistochemical features of glioblastoma (astrocytoma World Health Organization grade IV).

Efficacy of sorafenib in advanced renal cell carcinoma independent of prior treatment, histology or prognostic group.

AIM: To assess the response rate and safety of sorafenib in different subpopulations of patients with advanced renal cell carcinoma (RCC). METHODS: Single-arm open access trial. Key eligibility: advanced RCC with either clear-cell or non-clear-cell histopathology; progression on prior systemic chemotherapy or treatment naïve. Sorafenib was commenced at 400 mg twice daily continuously. RESULTS: A total 47 participants with metastatic RCC were treated with sorafenib. Overall, 1 participant experienced complete response, 6 (13%) had documented partial response (PR) and 29 (62%) had stable disease (SD) as the best response. Eight (17%) had non-clear-cell histopathology and five (10%) had sarcomatoid features. In the non-clear-cell histopathology cohort, five participants (62.5%) had SD. Twenty-three (49%) participants were treatment naïve; of these, 1/23 showed CR, 5/23 experienced PR and 13/23 had SD (clinical benefit: 83%). Overall, 14 (30%) and 22 (47%) participants had high-risk status according to MSKCC (Memorial Sloan-Kettering Cancer Center) and Heng prognostic scores, respectively. In the MSKCC poor prognostic group (14 participants), one participant had CR, two participants showed PR and eight participants had SD (clinical benefit: 79%). In Heng poor prognostic group (22 participants), 1 participant experienced CR, 2 participants showed PR and 13 had SD (clinical benefit: 73%). Hand-foot syndrome (53%), rash (47%), fatigue (42%), nausea (40%), anorexia (34%) and diarrhea (32%) were the most common adverse events. CONCLUSIONS: This study confirms the efficacy and tolerability of sorafenib in a different spectrum of advanced RCC patients including non-clear-cell histology, poor prognostic status and as first-line treatment.

Third-line chemotherapy in small-cell lung cancer: an international analysis.

INTRODUCTION: Small-cell lung cancer is an aggressive disease for which the mainstay of treatment is chemotherapy. Despite good initial responses most patients will relapse. Some will receive second-line therapy with clinical benefit, but for third-line chemotherapy there is little evidence to guide treatment decisions and the benefits of treatment are unknown. This study investigated the treatment of SCLC in the third-line setting. PATIENTS AND METHODS: An international, multicenter retrospective analysis of patients who received at least 3 lines of chemotherapy for their SCLC was performed. RESULTS: From 2000 to 2010, 120 patients were identified from 5 centers: median age 61, 40% (n = 72) limited stage, and 79% (n = 95) Eastern Cooperative Oncology Group performance status of 0 to 1. Only 22% of these patients received 3 distinct lines of chemotherapy. The remainder were rechallenged with a chemotherapy regimen used at least once previously. Six percent received platinum-based chemotherapy in all 3 lines. In third-line, response rate was 18% and median overall survival was 4.7 months. Factors associated with longer survival included normal baseline LDH levels and response to second-line chemotherapy. On multivariate analysis only normal baseline LDH retained statistical significance. Thirty-five patients went on to receive chemotherapy beyond the third line. CONCLUSION: Few SCLC patients receive 3 chemotherapy lines. Most patients were rechallenged with a similar regimen at least once. Response and survival in the third-line setting are modest. Lack of response to second-line chemotherapy and elevated baseline LDH level might predict lack of benefit from third-line treatment. This data set does not include patients receiving fewer lines for comparison.

USANZ: Time-trends in use and impact on outcomes of perioperative chemotherapy in patients treated with radical cystectomy for urothelial bladder cancer.

OBJECTIVE: To review time-trends in the use of perioperative chemotherapy and its impact on oncological outcomes in patients with bladder urothelial cancer (UC) at a single tertiary institution. PATIENTS AND METHODS: Using electronic and paper medical records, 89 patients were identified who underwent radical cystectomy with or without perioperative chemotherapy between 2004 and 2011 at Austin Health in Melbourne, Australia. Patient demographics, clinico-pathological characteristics and details of recurrence and death were assessed by retrospective chart review. Survival analysis was carried out using the Kaplan Meier method, with the impact of predictors assessed using Cox proportional hazard models. RESULTS: The median (range) age of this cohort was 65 (37-84) years, and 66 (74%) patients were male. Pathologic features included 68 (76%) pure UC, 21 (24%) mixed UC and 84 (94%) high grade tumours. On clinical staging, 63 (71%) patients had muscle-invasive bladder cancer (cT-stage ≥ T2), of whom 11 (17%) received neoadjuvant chemotherapy, with an increasing trend in use over time. Following radical cystectomy, pT-stage ≥ T3 and/or node positive were identified in 35 (39%) patients, of whom 16 (46%) received adjuvant chemotherapy. In addition, five patients with stage pT2 received adjuvant chemotherapy. Of the total cohort of patients, 31 (35%) suffered recurrences, and 33 died, 27 from urothelial carcinoma. On multivariate analysis, after adjusting for age, pT-stage and pN-stage, perioperative chemotherapy was associated with a significantly lower risk of recurrence [relative risk (RR) 0.41, p < 0.05], but not death from cancer or all causes. CONCLUSIONS: Perioperative chemotherapy, and in particular neoadjuvant chemotherapy, remains relatively under-utilised at our institution despite recent increases. The significant reduction in the risk of recurrence following treatment with perioperative chemotherapy with radical cystectomy highlights the importance of multi-modality treatment in bladder UC. Identifying barriers to more widespread implementation of perioperative chemotherapy is critical for enhancing outcomes in patients with bladder UC.

Pulmonary metastases: a rare manifestation of the most common cancer.

Basal cell carcinoma (BCC) is the most common human malignancy but rarely metastasises. We report on two patients with symptomatic lung metastases and a past history of recurrent BCC excisions. In our first patient, a heavy smoker with multiple lung lesions, histology of a resected nodule was first reported as non-small cell lung cancer but a repeat nodule biopsy a year later was recognised as a pulmonary metastasis from primary cutaneous BCC. Our second patient, a young never-smoker with two previous BCC, was confirmed as having a pulmonary metastasis from BCC on the lung resection specimen. Pulmonary metastasis from an unidentified primary site is a common clinical situation. These patients emphasise the importance of considering the most common cancer as a potential primary.

Comparison of toxicity and outcomes of concurrent radiotherapy with carboplatin/paclitaxel or cisplatin/etoposide in stage III non-small cell lung cancer.

Concurrent chemoradiotherapy (CCRT) has become the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC). The comparative merits of two widely used regimens: carboplatin/paclitaxel (PC) and cisplatin/etoposide (PE), each with concurrent radiotherapy, remain largely undefined. Records for consecutive patients with stage III NSCLC treated with PC or PE and ≥60 Gy chest radiotherapy between 2000 and 2011 were reviewed for outcomes and toxicity. Survival was estimated using the Kaplan-Meier method and Cox modeling with the Wald test. Comparison across groups was done using the student's t and chi-squared tests. Seventy-five (PC: 44, PE: 31) patients were analyzed. PC patients were older (median 71 vs. 63 years; P = 0.0006). Other characteristics were comparable between groups. With PE, there was significantly increased grade ≥3 neutropenia (39% vs. 14%, P = 0.024) and thrombocytopenia (10% vs. 0%, P = 0.039). Radiation pneumonitis was more common with PC (66% vs. 38%, P = 0.033). Five treatment-related deaths occurred (PC: 3 vs. PE: 2, P = 1.000). With a median follow-up of 51.6 months, there were no significant differences in relapse-free survival (median PC 12.0 vs. PE 11.5 months, P = 0.700) or overall survival (median PC 20.7 vs. PE 13.7 months; P = 0.989). In multivariate analyses, no factors predicted for improved survival for either regimen. PC was more likely to be used in elderly patients. Despite this, PC resulted in significantly less hematological toxicity but achieved similar survival outcomes as PE. PC is an acceptable CCRT regimen, especially in older patients with multiple comorbidities.

Urothelial cancers: using biology to improve outcomes.

Urothelial carcinoma (transitional cell carcinoma) is the most common malignancy of the urinary tract. Urothelial carcinoma of the bladder is a common disease but has traditionally been underrepresented in both public awareness and cancer research. The purpose of this review is to provide an outline of the recent updates in understanding of urothelial cancer etiology, particularly with regards to lower tract muscle-invasive disease, and to discuss the identified mutations in high- and low-grade disease. We will consider evidence for the current systemic therapies for muscle-invasive and metastatic disease and review the targeted therapies under investigation for advanced urothelial cancer.