Oncovascular surgery

Background

Surgical resection remains the cornerstone for the curative treatment of oncological disease. When a tumour mass encases a critical arterial or venous structure, successful symptom relief and long-term oncological control may be achieved through careful preoperative planning within a multi-disciplinary team incorporating oncological and vascular specialists. To highlight the strategic issues pertaining to the vascular management of these patients, this review addresses the principles in planning oncovascular surgery, namely where cancer resection necessitates concurrent ligation or reconstruction of a major vascular structure.

Design

A multiple electronic health database search was performed, including Medline, Embase, and Scopus.

Results

The published outcomes for different malignancies suggest that survival is dependent upon complete clearance of the primary pathology and tumour biology rather than vascular-related complications.

Conlcusion

Major vessel involvement of a tumour mass should not necessarily be considered a barrier to en bloc resection and hence curative surgery. Radical surgical resection may offer the only chance for cure or palliation for these patients. Detailed preoperative planning within an extended multi-disciplinary team that includes vascular specialists is essential for these complex patients.     

The use of palliative radiotherapy for bone metastasis

Background

The value of palliative radiotherapy (PRT) for bone metastases is well established, but little is known about its use in the general population.

Purpose

To describe the use of PRT for bone metastases in Ontario.

Materials and methods

This was a retrospective cohort study. Treatment records from all Ontario RT departments were linked to a population-based cancer registry to describe the use of PRT.

Results

12.2% of the 434,241 patients, who died of cancer in Ontario between 1984 and 2004, received at least one course of PRT for bone metastases in the last 2 years of life. The rate of use of PRT varied across the province (inter-county range, 8.2-18.6%). Older patients and residents of poorer areas were less likely to receive PRT (p < 0.0001). Patients diagnosed with cancer in a hospital with a radiotherapy facility and those who lived closer to a radiotherapy centre were more likely to receive PRT (p < 0.0001). Over the study period, the use of PRT decreased in breast cancer and myeloma, but increased in prostate cancer (p < 0.0001).

Conclusions

Access to PRT appears to be inequitable. More effort is required to make this useful treatment available to all those who would benefit from it.     

Adjuvant radiotherapy after extrapleural pneumonectomy for mesothelioma. Prospective analysis of a multi-institutional series

Background and purpose

To evaluate survival, locoregional control and toxicity in a series of 56 mesothelioma patients treated from May 2005 to May 2010 with post-operative radiotherapy after extrapleural pneumonectomy (EPP) in three Italian Institutions (Brescia, Florence, and Modena).

Material and methods

Fifty-six patients treated with adjuvant radiotherapy (RT) after EPP were analyzed. Four patients were treated with 3DCRT, 50 with IMRT and two with helical tomotherapy. Forty-five to 50 Gy in 25 fractions were given to the affected hemithorax and to ipsilateral mediastinum, with a simultaneous integrated boost to the sites of microscopically involved margins up to 60 Gy in 20/56 cases.

Results

Three year locoregional control (LRC), distant metastasis free (DMF), disease free (DF), disease specific (DSS) and overall survival (OS) rates are 90%, 66%, 57%, 62%, and 60%, respectively.

Conclusion

Postoperative RT with modern techniques is an effective method to obtain excellent local control and cure rates in mesothelioma patients submitted to EPP.     

Clinically significant human papilloma virus in squamous cell carcinoma of the head and neck in UK practice

Aims

The association between squamous cell carcinoma of the head and neck (HNSCC) and infection with human papilloma viruses (HPV) has created considerable interest. Rates of primary oropharyngeal cancers have shown increasing incidence and declining age at presentation over the last decade, believed to relate to infection with oncogenic or high-risk subtypes of HPV (HR-HPV). HR-HPV-associated tumours have reportedly improved outcomes when compared with HPV-negative cancers. Within the UK, rates of HR-HPV in HNSCC have not yet been reported.

Materials and methods

We analysed consecutive retrospective cases of oropharyngeal cancer presenting between 2004 and 2007.

Results

Thirty-seven per cent of 83 oropharyngeal tumours stained positively for p16^INK4A, a marker of HPV infection (73% tonsillar cancers being p16 ^INK4A positive, 30% tongue and 43% floor of mouth tumours). HPV16 DNA was demonstrated in 75% p16 ^INK4A cases. Despite being more advanced with higher T-stage and nodal burden at presentation, HR-HPV-associated HNSCC showed significantly improved rates of disease-free and overall survival, in particular with improved rates of response to radical radiotherapy.

Conclusion

HPV16 infection seems to be a clinically significant cause of oropharyngeal HNSCC in the UK and the collection of national data should be supported.     

Dose-volume analysis of locoregional recurrences in head and neck IMRT, as determined by deformable registration: A prospective multi-institutional trial

Background and purpose

Although IMRT for head and neck cancer is widely accepted, the implications of sparing normal tissue immediately adjacent to target volumes are not well known.

Materials and methods

Between 2002 and 2007, 124 patients with head and neck cancer were treated with surgery and postoperative IMRT (n = 79) or definitive RT (n = 45). Locoregional recurrences were analyzed for location relative to target volumes, and dosimetry.

Results

With a median follow-up of 26.1 months, a total of 16 locoregional recurrences were observed. The five-year actuarial locoregional disease-free survival was 82% [95% CI, 72-90%]. Analysis of 18 distinct sites of locoregional failure revealed that five of these failures were within the high dose clinical target volume (CTV), nine failures were at the margin of the CTV, and four recurrences were outside the CTV. The mean dose delivered to these recurrent volumes was 63.1 Gy [range: 57-68 Gy], while the mean dose to the coolest 1 cc within each recurrence was 60.0 Gy [range: 51-67 Gy]. There were two periparotid recurrences observed.

Conclusions

We observed excellent locoregional control rates overall. The majority of recurrences occur within high dose regions of the neck and not near the spared parotid glands.     

Erosive potential of saliva stimulating tablets with and without fluoride in irradiated head and neck cancer patients

Background

Patients irradiated in the head and neck region often suffer from severe dry mouth and use acidic saliva stimulating products, which may cause erosion of teeth.

Purpose

To determine saliva stimulating effects and erosive potential (EP) of acidic saliva stimulating tablets (Xerodent™) with and without fluoride in irradiated head and neck cancer patients.

Materials and method

Nineteen irradiated patients (median age 57 years) sucked Xerodent™ tablets with and without fluoride. Saliva collections were divided into three 10-min sessions in the sequence: unstimulated whole saliva, Xerodent™ stimulated saliva without fluoride, and with fluoride. Saliva pH was determined without loss of CO₂ and in combination with inorganic measures used to calculate the degree of saturation of hydroxyapatite (HAp) and fluorapatite (FAp). EP was determined directly in all saliva samples by monitored dissolution of HAp crystals.

Results

Saliva flow rates increased significantly (15-fold) when sucking both tablets (p < 0.001). Major changes in saliva composition caused undersaturation of HAp in some samples. However, no dissolution of HAp occurred in the saliva obtained with any of the two tablets. This was most likely due to the limited drop in pH resulting in saliva that was still supersaturated with respect to FAp.

Conclusion

Both Xerodent™ with and without fluoride were evaluated as non-erosive, however, for additional caries protection the fluoride variant is preferable.     

Increased F-deoxyglucose uptake in the lung during the first weeks of radiotherapy is correlated with subsequent Radiation-Induced Lung Toxicity (RILT): A prospective pilot study

Purpose

As Radiation-Induced Lung Toxicity (RILT) is dose-limiting for radiotherapy (RT) of lung cancer and current parameters are only moderately associated with RILT, we sought for novel parameters associated with RILT.

Patients and methods

In this prospective study, FDG-PET-CT scans were taken on days 0, 7 and 14 after initiation of high-dose RT in 18 patients with stage III non-small cell lung cancer. The maximal Standardized Uptake Value (SUV_max) in the lung outside of the GTV was used as a measure of FDG uptake. At the same time-points, the serum IL-6 concentrations were measured. RILT was defined as dyspnea score ?2 (CTCAE3.0).

Results

Six of 18 patients developed RILT. Before RT, SUV_max in the lung was not significantly different between patients who developed RILT and those who did not develop RILT. Patients who developed RILT post-radiation had a significant increased SUV on days 7 and 14 during RT, whereas the group that did not experience RILT showed no significant SUV changes. The SUV_max of the lungs increased significantly more in the group that later developed RILT compared to those who did not develop RILT. Neither the IL-6 concentration nor the mean lung dose was associated with RILT.

Conclusions

The increase in FDG uptake in the normal lung early during RT was highly associated with the subsequent development of clinical RILT. This may help to identify patients at high risk for RILT at a time when adjustments of the treatment or strategies to prevent RILT are still possible.     

Low ERCC1 mRNA and protein expression are associated with worse survival in cervical cancer patients treated with radiation alone

Purpose

To evaluate the association of excision repair cross-complementation group 1 (ERCC1) expression, using both mRNA and protein expression analysis, with clinical outcome in cervical cancer patients treated with radical radiation therapy (RT).

Experimental design

Patients (n = 186) with locally advanced cervical cancer, treated with radical RT alone from a single institution were evaluated. Pre-treatment FFPE biopsy specimens were retrieved from 112 patients. ERCC1 mRNA level was determined by real-time PCR, and ERCC1 protein expression (FL297, 8F1) was measured using quantitative immunohistochemistry (AQUA®). The association of ERCC1 status with local response, 10-year disease-free (DFS) and overall survival (OS) was analyzed.

Results

ERCC1 protein expression levels using both FL297 and 8F1 antibodies were determined for 112 patients; mRNA analysis was additionally performed in 32 patients. Clinical and outcome factors were comparable between the training and validation sets. Low ERCC1 mRNA expression status was associated with worse OS (17.9% vs 50.1%, p = 0.046). ERCC1 protein expression using the FL297 antibody, but not the 8F1 antibody, was significantly associated with both OS (p = 0.002) and DFS (p = 0.010). After adjusting for pre-treatment hemoglobin in a multivariate analysis, ERCC1 FL297 expression status remained statistically significant for OS [HR 1.9 (1.1-3.3), p = 0.031].

Conclusions

Pre-treatment tumoral ERCC1 mRNA and protein expression, using the FL297 antibody, are predictive factors for survival in cervical cancer patients treated with RT, with ERCC1 FL297 expression independently associated with survival. These results identify a subset of patients who may derive the greatest benefit from the addition of cisplatin chemotherapy.     

The impact of postmastectomy radiotherapy on local control in patients with invasive lobular breast cancer

Purpose

The aim of this population-based study was to examine the impact of postmastectomy radiotherapy on the risk of local recurrence in patients with invasive lobular breast cancer (ILC).

Methods

The population-based Eindhoven Cancer Registry was used to select all patients with ILC, who underwent mastectomy in five general hospitals in the southern part of the Netherlands between 1995 and 2002. Of the 499 patients 383 patients fulfilled the eligibility criteria. Of these patients, 170 (44.4%) had received postmastectomy radiotherapy. The median follow-up was 7.2 years. Fourteen patients (3.7%) were lost to follow-up.

Results

During follow-up 22 patients developed a local recurrence, of whom 4 had received postmastectomy radiotherapy. The 5-year actuarial risk of local recurrence was 2.1% for the patients with and 8.7% for the patients without postmastectomy radiotherapy. After adjustment for age at diagnosis, tumour stage and adjuvant systemic treatment, the patients who underwent postmastectomy radiotherapy were found to have a more than 3 times lower risk of local recurrence compared to the patients without (Hazard Ratio 0.30; 95% Confidence Interval: 0.10-0.89).

Conclusion

Local control is excellent for patients with ILC who undergo postmastectomy radiotherapy and significantly better than for patients not receiving radiotherapy.     

The cost of radiotherapy in a decade of technology evolution

Purpose

To quantify changes in radiotherapy costs occurring in a decade of medical-technological evolution.

Materials and methods

The activity-based costing (ABC) model of the University Hospitals Leuven (UHL) radiotherapy (RT) department was adapted to current RT standards. It allocated actual resource costs to the treatments based on the departmental work-flow and patient mix in 2009. A benchmark with the former model analyzed the cost increases related to changes in RT infrastructure and practice over 10 years.

Results

A considerable increase in total RT costs was observed, resulting from higher capital investments (96%) and personnel cost (103%), the latter dominating the total picture. Treatment delivery remains the most costly activity, boosted by the cost of improved quality assurance (QA), 23% of total product costs, coming along with more advanced RT techniques. Hence, cost increases at the product level are most obvious for complex treatments, such as intensity-modulated radiotherapy (IMRT), representing cost increases ranging between 38% and 88% compared to conformal approaches.

Conclusions

The ABC model provides insight into the financial consequences of evolving technology and practice. Such data are a mandatory first step in our strive to prove RT cost-effectiveness and thus support optimal reimbursement and provision of radiotherapy departments.     

A study of middle ear function in the treatment of nasopharyngeal carcinoma with IMRT technique

Purpose

This study evaluates the difference in damage to middle ear function with CRT and IMRT techniques in the treatment of nasopharyngeal carcinoma (NPC). We explore the isthmus of the Eustachian tube (ET) as the key anatomic site for the prevention of radiation-induced otitis media with effusion.

Methods and materials

Eighty-two patients with NPC were divided into two groups: 40 patients treated with CRT and 42 patients treated with IMRT. The difference between dosage over the middle ear cavity and the isthmus of the ET was evaluated in both CRT group and IMRT group. All patients underwent hearing tests including pure tone audiometry and impedance audiometry before and after RT.

Results

The dosage difference to the middle ear cavity and isthmus between these two groups was statistically significant (p < 0.05). The difference in hearing test results between these two groups was also statistically significant (p < 0.05). If we limited the dose to the middle ear cavity under 34 Gy and the dose to the isthmus under 53 Gy with IMRT, we may decrease radiation-induced OME even with the larger 2.25 Gy fraction size.

Conclusions

IMRT may have better protected the middle ear function compared with the CRT technique, even with larger fraction sizes than for the conventional CRT technique.     

General practitioners and referral for palliative radiotherapy: A population-based survey

Background and purpose

The suspicion exists that the referral rate for palliative radiotherapy (RT) is too low. RT, especially in a short series, is an essential and established modality within palliative cancer care for localised symptoms.

Material and methods

Questionnaires to evaluate the knowledge of palliative RT were sent to the 1100 general practitioners (GP’s) in the area of the Comprehensive Cancer Centre South in the Netherlands, covering about 2.6 million inhabitants. Four hundred and ninety-eight questionnaires were evaluated.

Results

Forty-six percent of the respondents had cared for patients referred for palliative RT in the last two years. Knowledge about the effects of palliative RT on bone metastases and spinal cord compression was good but about other palliative indications it was moderate to poor. Determinants of the actual referral for palliative RT were mainly patient related. GPs considered their own knowledge to be poor with only 10% reporting previous RT education.

Conclusions

It is absolutely necessary to inform GPs about the possibility of short series of palliative irradiation in order to improve their information for symptomatic cancer patients about all possibilities for palliative treatment.     

Robotic system-based fractionated stereotactic radiotherapy in locally recurrent nasopharyngeal carcinoma

Purpose

We reviewed survival, local control, and toxicity in patients with locally recurrent nasopharyngeal carcinoma (NPC) who had been treated with fractionated stereotactic radiotherapy (FSRT).

Materials and methods

Between June 2002 and March 2008, we retrospectively reviewed 35 patients with locally recurrent NPC treated using FSRT with CyberKnife. Gross tumor volumes ranged from 2.6 to 64.0 ml (median, 7.9 ml). Radiation doses were prescribed at the isodose line (75-84% of the maximum dose; median, 80%). The prescribed dose of FSRT ranged from 24 to 45 Gy (median, 33 Gy) in three or five fractions.

Results

The overall survival (OS) rate, local failure-free survival (LFFS) rate, and disease progression-free survival (DPFS) rate at 5 years were 60%, 79%, and 74%, respectively. Twenty-three patients achieved complete response after FSRT. Only T stage at recurrence was an independent prognostic factor for OS and DPFS. Five patients exhibited severe late toxicity (Grade 4 or 5).

Conclusions

With regard to OS and LFFS, our study provided favorable outcomes. The incidence of severe late toxicities was acceptable in our study. FSRT would be considered as the alternative treatment of choice in re-irradiation for locally recurrent NPC.     

8 Gy single-dose radiotherapy is effective in metastatic spinal cord compression: Results of a phase III randomized multicentre Italian trial

Background and purpose

In a previous randomized trial we showed that the short-course radiotherapy (RT) regimen of 8 Gy × 2 was feasible in patients with metastatic spinal cord compression (MSCC) and short life expectancy. This phase III trial was planned to determine whether in the same category of patients 8 Gy single-dose is as effective as 8 Gy × 2.

Materials and methods

Three hundred and twenty-seven patients with MSCC and short life expectancy were randomly assigned to a short-course of 8 Gy × 2 or to 8 Gy single-dose RT. Median follow-up was 31 months (range, 4-58).

Results

A total of 303 (93%) patients are assessable, 150 treated with the short-course and 153 with the single-dose RT. No difference in response was found between the two RT schedules adopted. Median duration of response was 5 and 4.5 months for short-course and single-dose RT (p = 0.4), respectively. The median overall survival was 4 months for all cases. Light acute toxicity was registered in a minority of cases. Late toxicity was never recorded.

Conclusions

Both RT schedules adopted were effective. As already shown in several trials evaluating RT regimens in uncomplicated painful bone metastases, also MSCC patients may achieve palliation with minimal toxicity and inconvenience with a single-dose of 8 Gy.     

Histopathological and immunohistochemical features associated with clinical response to neoadjuvant gefitinib therapy in early stage non-small cell lung cancer

Background

Matrix metalloproteinases (MMPs) are considered important players in angiogenesis and cancer progression. Several drugs developed for targeting MMPs have until now been without clinical efficacy. As both malignant cells and cells of the surrounding stroma contribute to tumor growth, we have explored the impact of MMP-2, -7 and -9 expression in both the tumor and stromal compartment of non-small-cell lung cancers (NSCLC).

Patients and methods

From 335 unselected stage I to IIIA NSCLC carcinomas, duplicate tumor and tumor-associated stromal cores were collected in tissue microarrays (TMAs). Immunohistochemistry was used to detect the expression of MMP-2, -7 and -9 in tumor and stromal cells.

Results

In univariate analyses, high tumor cell MMP-7 expression (P = 0.029) and high stromal MMP-9 expression (P = 0.001) were positive prognostic factors. In the multivariate analysis, high tumor cell MMP-7 expression (HR 1.58, CI 1.08-2.32, P = 0.020) and high stromal MMP-9 expression (HR 1.92, CI 1.25-2.96, P = 0.003) were independent positive prognostic factors for disease-specific survival.

Conclusion

High levels of MMP-7 in tumor cells and high levels of MMP-9 in tumor associated stroma were independent positive prognostic factors in NSCLC patients.     

Prognostic effect of stromal lymphocyte infiltration in thymic carcinoma

Background

The purpose of this study was to clarify the relationship between the tumor infiltrating lymphocytes and clinical outcome in patients with thymic carcinoma.

Methods

Tissue specimens from 32 patients who underwent surgical resection for thymic carcinoma were immunohistochemically analyzed for CD4, CD8 and CD20 expression.

Results

Tumor-infiltrating lymphocytes were generally more abundant in the stroma. The patients with low CD4+ lymphocytes (p = 0.037) and low CD20+ lymphocytes (p = 0.045) within tumor stroma showed poor survival. Furthermore, concurrent low levels of CD4+ and CD20+ (p = 0.014), CD8+ and CD20+ (p = 0.025), and, CD4+, CD8+, and CD20+ (p = 0.025) in tumor stroma were significantly associated with poor prognosis when compared to the others group.

Conclusion

Our results indicate that infiltrating CD4+, CD8+, and CD20+ lymphocytes in cancer stroma may cooperate to suppress cancer progression and their presence together appear to be prognostic factor in thymic carcinoma.     

Metabolic control probability in tumour subvolumes or how to guide tumour dose redistribution in non-small cell lung cancer (NSCLC): An exploratory clinical study

Purpose

To characterize the relationship between pre-radiotherapy ¹⁸Fluorodeoxyglucose (FDG) uptake in a tumour voxel, radiation dose and the probability to achieve metabolic control in the tumour voxel after radiotherapy.

Materials and methods

Thirty-nine patients with inoperable stage I-III non-small cell lung cancer, treated with radiotherapy (RT) alone or sequential chemo radiation were analysed retrospectively. Twenty-two showed metabolic active areas in the tumour 3 months post-radiotherapy, which is known to be a surrogate for persistent local tumour failure and worse survival. Pre- and post-RT FDG-PET-CT scans were registered and the metabolic active zones within the tumour after RT were projected on the pre-RT scan. Multi-level logistic regression was performed to determine the relation between the FDG uptake if a voxel pre-RT and its metabolic state after RT.

Results

The probability that a voxel is metabolically controlled (mVCP), decreased significantly with increasing FDG uptake in a voxel (SUV) (OR = 0.72), increasing tumour volume (20 cm³) (OR = 0.89) and increasing dose (Gy) (OR = 0.99). Inter-patient differences in mVCP were substantial.

Conclusion

A methodology was presented to derive relationships between FDG uptake, dose and metabolic control. Although no strong dose effect relation was demonstrated, mVCP decreased with increasing FDG uptake and tumour volume.     

Soy isoflavones radiosensitize lung cancer while mitigating normal tissue injury

Background

We have demonstrated that soy isoflavones radiosensitize cancer cells. Prostate cancer patients receiving radiotherapy (RT) and soy tablets had reduced radiation toxicity to surrounding organs. We have now investigated the combination of soy with RT in lung cancer (NSCLC), for which RT is limited by radiation-induced pneumonitis.

Methods

Human A549 NSCLC cells were injected i.v. in nude mice to generate lung tumor nodules. Lung tumor-bearing mice were treated with left lung RT at 12 Gy and with oral soy treatments at 1 mg/day for 30 days. Lung tissues were processed for histology.

Results

Compared to lung tumor nodules treated with soy isoflavones or radiation, lung tissues from mice treated with both modalities showed that soy isoflavones augmented radiation-induced destruction of A549 lung tumor nodules leading to small residual tumor nodules containing degenerating tumor cells with large vacuoles. Soy isoflavones decreased the hemorrhages, inflammation and fibrosis caused by radiation in lung tissue, suggesting protection of normal lung tissue.

Conclusions

Soy isoflavones augment destruction of A549 lung tumor nodules by radiation, and also mitigate vascular damage, inflammation and fibrosis caused by radiation injury to normal lung tissue. Soy could be used as a non-toxic complementary approach to improve RT in NSCLC.     

Carbogen and nicotinamide in locally advanced bladder cancer: Early results of a phase-III randomized trial

Purpose

Phase II studies in laryngeal and bladder carcinoma of accelerated radiotherapy with carbogen and nicotinamide (RT + CON) suggested a therapeutic advantage. Therefore, a randomized phase-III trial of RT + CON in locally advanced bladder carcinoma compared to radiotherapy (RT) alone was undertaken.

Methods

One hundred and sixty-five patients with muscle-invasive transitional cell bladder carcinoma were randomized to RT alone and 168 to RT + CON. This paper reports on compliance and toxicity to nicotinamide (NAM) and carbogen and on early radiation-induced adverse bowel and urinary events.

Results

Of those receiving RT + CON, 65-69% accepted all doses of NAM. Sixty-four percent of patients presented Grade ?1 NAM toxicity (nausea or vomiting), which was severe in 13%. Compliance to carbogen was 85% and none (32 fractions) and 2% (20 fractions) of patients presented severe toxicity. The highest prevalence of severe radiation acute morbidity was seen for urinary frequency (RT: 18% and RT + CON: 15%) and for diarrhea (RT: 3% and RT + CON: 5%).

Conclusions

There is no indication of an increase in radiation-induced morbidity by combining the tumour radiosensitizers carbogen and nicotinamide with radiotherapy. Late morbidity and treatment outcome will ultimately determine if there is a therapeutic benefit.     

ASCL1-coexpression profiling but not single gene expression profiling defines lung adenocarcinomas of neuroendocrine nature with poor prognosis

Background

Lung adenocarcinoma is heterogeneous regarding histology, etiology and prognosis. Although there have been several attempts to find a subgroup with poor prognosis, it is unclear whether or not adenocarcinoma with neuroendocrine (NE) nature has unfavorable prognosis.

Materials and methods

To elucidate whether a subtype of adenocarcinoma with NE nature has poor prognosis, we performed gene expression profiling by cDNA microarray for 262 Japanese lung cancer and 30 normal lung samples, including 171 adenocarcinomas, 56 squamous cell carcinomas and 35 NE tumors. A co-expression gene set with ASCL1, an NE master gene, was utilized to classify tumors by non-negative matrix factorization, followed by validation using an ASCL1 knock-down gene set in DMS79 cells as well as an independent cohort (n = 139) derived from public microarray databases as a test set.

Results

The co-expression gene set classified the adenocarcinomas into alveolar cell (AL), squamoid, and NE subtypes. The NE subtype, which clustered together almost all the NE tumors, had significantly poorer prognosis than the AL subtype that clustered with normal lung samples (p = 0.0075). The knock-down gene set also classified the 171 adenocarcinomas into three subtypes and this NE subtype also had the poorest prognosis. The co-expression gene set classified the independent database-derived American cohort into two subtypes, with the NE subtype having poorer prognosis. None of the single NE gene expression was found to be linked to survival difference.

Conclusion

Co-expression gene set with ASCL1, rather than single NE gene expression, successfully identifies an NE subtype of lung adenocarcinoma with poor prognosis.