An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma.

This corrects the article DOI: 10.1038/bjc.2017.85.

An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive tumour originating in the thoracic mesothelium. Prognosis remains poor with 9- to 12-month median survival, and new targets for treatments are desperately needed. METHODS: Utilising an RNA interference (RNAi)-based screen of 40 genes overexpressed in tumours, including genes involved in the control of cell cycle, DNA replication and repair, we investigated potential therapeutic targets for MPM. Following in vitro characterisation of the effects of target silencing on MPM cells, candidates were assessed in tumour samples from 154 patients. RESULTS: Gene knockdown in MPM cell lines identified growth inhibition following knockdown of NDC80, CDK1 and PLK1. Target knockdown induced cell-cycle arrest and increased apoptosis. Using small-molecule inhibitors specific for these three proteins also led to growth inhibition of MPM cell lines, and Roscovitine (inhibitor of CDK1) sensitised cells to cisplatin. Protein expression was also measured in tumour samples, with markedly variable levels of CDK1 and PLK1 noted. PLK1 expression in over 10% of cells correlated significantly with a poor prognosis. CONCLUSION: These results suggest that RNAi-based screening has utility in identifying new targets for MPM, and that inhibition of NDC80, CDK1 and PLK1 may hold promise for treatment of this disease.

Phosphorylated Akt expression is a prognostic marker in early-stage non-small cell lung cancer.

AIMS: To determine the prognostic significance of pAkt expression in order to identify high-risk stage IB patients with non-small cell lung cancer (NSCLC) in an exploratory study. METHODS: We identified 471 consecutive patients with stage IB primary NSCLC according to the American Joint Commission on Cancer 6th edition tumour-node-metastasis (TNM) staging system, who underwent surgical resection between 1990 and 2008. Patients who received neoadjuvant or adjuvant treatments were excluded. Pathology reports were reviewed, and pathological characteristics were extracted. Expression of phosphorylated Akt (pAkt) in both cytoplasmic and nuclear locations was assessed by immunohistochemistry, and clinicopathological factors were analysed against 10-year overall survival using Kaplan-Meier and Cox proportional hazards model. RESULTS: 455 (96.6%) cancers were adequate for pAkt immunohistochemical analysis. The prevalence of pAkt expression in the cytoplasm and nucleus of the cancers was 60.7% and 43.7%, respectively. Patients whose cancers expressed higher levels of cytoplasmic pAkt had a trend towards longer overall survival than those with lower levels (p=0.06). Conversely, patients whose cancers expressed higher levels of nuclear pAkt had a poorer prognosis than those with lower levels of expression (p=0.02). Combined low cytoplasmic/high nuclear expression of pAkt was an independent predictor of overall survival (HR=2.86 (95% CI 1.35 to 6.04); p=0.006) when modelled with age (HR=1.05 (95% CI 1.03 to 1.07); p<0.001), extent of operation (HR=2.11 (95% CI 1.48 to 3.01); p<0.001), visceral pleural invasion (HR=1.63 (95% CI 1.24 to 2.15); p<0.001), gender, tumour size, histopathological type and grade (p>0.05). CONCLUSIONS: Level of expression of pAkt in the cytoplasm and nucleus is an independent prognostic factor that may help to select patients with high-risk disease.

Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is recalcitrant to treatment and new approaches to therapy are needed. Reduced expression of miR-15/16 in a range of cancer types has suggested a tumour suppressor function for these microRNAs, and re-expression has been shown to inhibit tumour cell proliferation. The miR-15/16 status in MPM is largely unknown. MATERIALS AND METHODS: MicroRNA expression was analysed by TaqMan-based RT-qPCR in MPM tumour specimens and cell lines. MicroRNA expression was restored in vitro using microRNA mimics, and effects on proliferation, drug sensitivity and target gene expression were assessed. Xenograft-bearing mice were treated with miR-16 mimic packaged in minicells targeted with epidermal growth factor receptor (EGFR)-specific antibodies. RESULTS: Expression of the miR-15 family was consistently downregulated in MPM tumour specimens and cell lines. A decrease of 4- to 22-fold was found when tumour specimens were compared with normal pleura. When MPM cell lines were compared with the normal mesothelial cell line MeT-5A, the downregulation of miR-15/16 was 2- to 10-fold. Using synthetic mimics to restore miR-15/16 expression led to growth inhibition in MPM cell lines but not in MeT-5A cells. Growth inhibition caused by miR-16 correlated with downregulation of target genes including Bcl-2 and CCND1, and miR-16 re-expression sensitised MPM cells to pemetrexed and gemcitabine. In xenograft-bearing nude mice, intravenous administration of miR-16 mimics packaged in minicells led to consistent and dose-dependent inhibition of MPM tumour growth. CONCLUSIONS: The miR-15/16 family is downregulated and has tumour suppressor function in MPM. Restoring miR-16 expression represents a novel therapeutic approach for MPM.

Pulmonary metastatic melanoma -- the survival benefit associated with positron emission tomography scanning.

OBJECTIVE: Positron emission tomography (PET) scanning is more sensitive at detecting metastatic disease than conventional radiological techniques. For patients with pulmonary metastatic melanoma, we investigate if PET scanning to detect occult extra pulmonary disease prior to thoracotomy and metastectomy is associated with improved survival compared to patients staged by conventional radiology. METHODS: Between November 1984 and December 1999, 121 patients (90 males, 31 females) have undergone a thoracotomy and pulmonary metastectomy for metastatic melanoma. The age range was 19-84 years (mean 57, median 59). In every case all palpable nodules were removed and the diagnosis confirmed histologically. A total of 68 (56%) patients had a PET scan preoperatively, 53 (44%) underwent conventional or nuclear imaging. Patients with only radiologically isolated pulmonary disease are included. RESULTS: Survival is 100% complete and totals 238 pt/years (mean 2.2 years, median 1.4 years). Survival (+/-SE) at 1, 3, 5 and 7 years for all patients is 68% (+/-4.5) (n=67), 36.6% (+/-5.2) (n=27), 22.1% (+/-4.8) (n=15) and 13.5% (+/-4.2) (n=7), respectively. Survival (+/-SE) was significantly better at 3 and 5 years in patients who underwent a PET scan preoperatively (Log rank P=0.002). There was no significant difference in survival by 7 years. CONCLUSIONS: There is a significant survival benefit associated with excluding extra pulmonary disease using a PET scan prior to thoracotomy and metastectomy. We recommend that PET scanning be used in the investigation of patients with pulmonary metastatic melanoma prior to metastectomy.

Resection of residual pulmonary masses after chemotherapy in patients with metastatic non-seminomatous germ cell tumours.

BACKGROUND: Resection of residual post-chemotherapy pulmonary masses in patients with non-seminomatous germ cell tumours gives therapeutic benefit and prognostic information. AIM: This study was undertaken to review the experience of this intervention in a single teaching hospital. METHODS: The Germ Cell Database of the Sydney Cancer Centre was searched for all patients who had undergone excision of pulmonary metastases. These patient records were subsequently reviewed. RESULTS: Between 1976 and 1999, 15 patients underwent a combined total of 19 thoracotomies for resection of residual tumour mass after cisplatin-based chemotherapy. The primary tumour histology included mature teratoma in 47% (7 of 15) of patients. Prior to chemotherapy, 73% (11 of 15) of patients had elevated serum levels of alpha-fetoprotein (median 180 ng/mL) and 60% (9 of 15) of patients had elevated beta-human chorionic gonadotropin (median 672 IU/L). The median length of hospital stay related to thoracotomy was 7 days. There were two surgical complications, a prolonged air leak and a residual pleural effusion. Pathology of residual pulmonary masses revealed necrosis alone in 37% (7 of 19) of procedures, mature teratoma alone in 32% (6 of 19) of procedures and viable tumour in 32% (6 of 19) of procedures. Of those with viable tumour, three achieved long-term complete response (CR), two died of progressive disease (PD) and one is alive with PD. Of those with teratoma, two achieved CR and one relapsed. The long-term CR rate was 80% (12 of 15 patients). The median follow up was 10 years (range 0.75-17.5 years). Four patients died, two of PD and two of cardiovascular disease while in CR. CONCLUSION: At this institution, thoracotomy for residual pulmonary masses was well tolerated, with a high cure rate.

Thymoma: trends over time.

BACKGROUND: This is a review of a series of patients who presented with thymoma over the most recent 20-year period. Changes and trends in disease patterns were documented. METHODS: Data were collated retrospectively but all pathology slides were reviewed. Survival functions were estimated using the Kaplan-Meier method. RESULTS: Seventy-one patients had a partial or total thymectomy during this period for a thymoma. Average age was 55 years. Twenty-three patients (32%) had myaesthenia gravis. Eighteen patients (25%) were asymptomatic. Thirty-three patients (47%) had stage 1 disease. Complete resection was achieved in 60 patients (85%). Five-year survival was 88%. Fifty percent of patients with myesthenia gravis showed improvement in symptoms. CONCLUSIONS: Five- and 10-year survival rates in this study are better than in other series. We attribute this to an increasing number of patients with stage 1 and stage 2 disease, particularly those with myasthenia gravis who now have screening computer tomography, and also to the surgical intent of aiming to achieve complete resection even if excision of adjacent tissue is required.

Surgical resection for pulmonary metastases from colorectal cancer.

BACKGROUND: Isolated pulmonary metastases from colorectal cancer are rare. The present study reports on the 15-year experience of the Royal Prince Alfred Unit and discusses means of improving survival outcomes. METHODS: This was a retrospective review, over a 15-year period, of 41 patients who had resectable pulmonary metastases of colorectal origin. RESULTS: Most were asymptomatic at the time of diagnosis. Seventy-two per cent had solitary metastases. The most common procedure performed was a lobectomy. Median follow up was 21 months. Five-year survival was 24%. There were no significant prognostic indicators except for the ability to achieve clear surgical margins. CONCLUSION: Morbidity and mortality have not altered significantly over time. But an improved selection process such as the use of preoperative positron emission tomography will potentially improve survival outcomes.

Video-assisted thoracoscopy.

Recent advances in video-imaging and minimally invasive surgical instrumentation have expanded the role of thoracoscopy in the diagnosis and treatment of intrathoracic conditions. This prospective study describes the use of video-assisted thoracoscopy (VAT) in 100 consecutive patients. There were 70 males and 30 females with a mean age of 54.6. They underwent 103 VAT procedures with 41 thoracoscopic biopsies of lung, pleural, chest wall and mediastinal abnormalities, 32 for treatment of recurrent or persistent pneumothorax, 18 for thoracoscopic assessment of pulmonary and pleural tumours and 12 for thoracoscopic resection of peripheral lung lesions, chest wall, mediastinal and pleural tumours. Eighty-one patients had VAT procedures alone while the remaining 19 had VAT proceeding to thoracotomy. The mean operating time for VAT alone was 51 min (range 30-135 min). There were no operative deaths. There were 8 significant complications from which patients recovered fully. Patients who underwent VAT alone were shown to have earlier postoperative mobilization, reduction in parenteral analgesic requirement and reduced length of hospital stay compared to patients undergoing additional thoracotomy. A telephone survey of patients on returning home showed that patients undergoing VAT alone returned to full activity earlier than those who had thoracotomy (mean 9.0 vs mean 19.4 days). This study confirms that VAT is a safe and effective procedure in the management of pulmonary, mediastinal and pleural disease and the treatment of persistent and recurrent pneumothorax. Its role in the resection of pulmonary malignancy remains to be defined.

Devolved clinical management and casemix.

Devolved clinical management aims at greater medical and nursing involvement in the management of health resources and focuses on achieving measurable improvements in patient care through better use of resources. It permits the major drivers of the health care system (doctors), in collaboration with the major direct care providers (nurses), to be not only effective at allocating resources but also effective resource users. Casemix is a classification of patient care episodes based principally on resource use and can assist in the process of managing health services. We discuss the relationship between devolved clinical management and casemix systems. Health care organisations must move towards devolved clinical management, with a greater focus on the patient and a greater emphasis on accountability among all clinical disciplines.

Primary lung cancer invading the chest wall.

Chest wall invasion per se does not preclude resection nor indicate incurability in patients with non-small cell lung cancer. Preoperative assessment identifies patients without evidence of distant metastases, spinal invasion, or regional lymph node metastases. At thoracotomy, these selected patients usually undergo complete resection of tumor with an expected 5-year survival, in the absence of lymph node involvement, in excess of 50% when en bloc resection of the lung and involved chest wall is performed. Neither radiotherapy nor chemotherapy appear to impact on this survival.

Perforation of the esophagus by a fish bone leading to cardiac tamponade.

A 32-year-old woman swallowed a fish bone and presented to the hospital 3 days later with chest pain and fever. While in the hospital, she became hypotensive. A computed tomographic scan showed a fish bone penetrating from the esophagus into the pericardium. The fish bone was removed at urgent thoracotomy with immediate relief of her circulatory compromise. At the time of the operation, the fish bone was noted to be abrading the surface of the left atrium. We report this case of cardiac tamponade secondary to a perforated esophagus after foreign body ingestion.

Combination chemotherapy with cisplatin, vindesine and mitomycin-C for advanced, inoperable non-small-cell lung cancer.

OBJECTIVES: To assess the activity of chemotherapy with cisplatin, vindesine and mitomycin-C (PVM) in advanced non-small-cell lung cancer (NSCLC) and to test the feasibility of preemptive therapy with PVM. DESIGN AND SETTING: A phase II clinical trial of PVM in patients with NSCLC treated at the Royal Prince Alfred Hospital between June 1987 and July 1990. PATIENTS: Forty-one patients with advanced, inoperable or recurrent NSCLC--22 women, 19 men, with a median age of 51 years. Thirteen patients had been treated previously with radiotherapy and/or surgery; 18 had extrathoracic metastases. Four patients previously deemed inoperable were treated preemptively with PVM before proceeding to radical surgery. INTERVENTIONS: Cisplatin 100 mg/m2, vindesine 5 mg and mitomycin-C 8 mg/m2, all given intravenously on Day 1, with vigorous hydration and antiemetic therapy. Cycles were repeated every four weeks. MAIN OUTCOME MEASURES: Objective tumour response to treatment, patient survival time, time to treatment failure, and treatment toxicity. RESULTS: There was one complete tumour response to PVM and 15 partial responses; 14 patients had stable disease and nine had progressive disease--yielding an objective response rate (complete plus partial responses) of 39% (16/41; 95% confidence interval [CI], 24%-56%). Responses were documented in all histological subgroups, in both locally advanced and disseminated disease, and in recurrent disease. Median survival of the group was six months (95% CI, 5-10 months; range, 0.5-19+ months), and is unchanged by exclusion of the four patients treated before surgery. Seven of the 41 patients (17%) survived 12 months or longer. Median time to treatment failure in patients who had an objective response was six months (95% CI, 5-10 months). Grade 3 or 4 nausea and vomiting occurred in 21 patients (51%). Haematological, renal and neurological toxicity were not major problems; there were no deaths from treatment toxicity. CONCLUSION: PVM is an active regimen in advanced NSCLC and can produce durable remissions. The potential palliative effects of PVM in incurable disease must be weighed against the risk of subjective toxicity.

Malignancy in a massive localized fibrous tumour of pleura.

Localized fibrous tumour of pleura is a rare condition. Most follow a benign course and are an incidental finding during routine chest X-ray. A small proportion of these tumours are malignant and have characteristic clinical and histopathological features. This case report is of a 65 year old woman who presented with respiratory symptoms and polyarthropathy, and had a subsequent resection of a massive pleural tumour with features suggestive of malignancy.

Intrapleural bupivacaine in the control of postthoracotomy pain.

A randomized, double-blind trial was conducted to determine the effectiveness of intrapleural bupivacaine hydrochloride in the management of pain after thoracotomy. Thirty-three men and 7 women with a mean age of 62 years (range, 21 to 76 years) undergoing elective posterolateral thoracotomy were randomly allocated preoperatively to either a study group receiving 20 mL of 0.25% bupivacaine or a control group receiving 20 mL of 0.9% saline solution through a pleural catheter every 4 hours. Patients received supplementary doses of intramuscular papaveretum as required. Assessment of pain, somnolence, and breathing capacity was performed after the intrapleural injections at 4, 24, 48, and 72 hours postoperatively. Pain assessment, as measured by a linear analog scale, was lower in the bupivacaine group at all times, reaching significance at 4, 24, and 72 hours (p less than 0.05). The forced vital capacity and forced expiratory volume in 1 second at 6 weeks postoperatively remained significantly lower than preoperatively (p less than 0.05). The fall in forced vital capacity from this postoperative level was significantly less in the bupivacaine group at 4, 24, and 48 hours, and the fall in forced expiratory volume in 1 second was significantly less at 4 and 48 hours in the treated group. When used in conjunction with doses of parenteral narcotic, intrapleural bupivacaine gives better pain control with less respiratory depression than intermittent doses of narcotic alone.