Machine learning-based immune phenotypes correlate with STK11/KEAP1 co-mutations and prognosis in resectable NSCLC: a sub-study of the TNM-I trial.

BACKGROUND: We aim to implement an immune cell score model in routine clinical practice for resected non-small-cell lung cancer (NSCLC) patients (NCT03299478). Molecular and genomic features associated with immune phenotypes in NSCLC have not been explored in detail. PATIENTS AND METHODS: We developed a machine learning (ML)-based model to classify tumors into one of three categories: inflamed, altered, and desert, based on the spatial distribution of CD8+ T cells in two prospective (n = 453; TNM-I trial) and retrospective (n = 481) stage I-IIIA NSCLC surgical cohorts. NanoString assays and targeted gene panel sequencing were used to evaluate the association of gene expression and mutations with immune phenotypes. RESULTS: Among the total of 934 patients, 24.4% of tumors were classified as inflamed, 51.3% as altered, and 24.3% as desert. There were significant associations between ML-derived immune phenotypes and adaptive immunity gene expression signatures. We identified a strong association of the nuclear factor-κB pathway and CD8+ T-cell exclusion through a positive enrichment in the desert phenotype. KEAP1 [odds ratio (OR) 0.27, Q = 0.02] and STK11 (OR 0.39, Q = 0.04) were significantly co-mutated in non-inflamed lung adenocarcinoma (LUAD) compared to the inflamed phenotype. In the retrospective cohort, the inflamed phenotype was an independent prognostic factor for prolonged disease-specific survival and time to recurrence (hazard ratio 0.61, P = 0.01 and 0.65, P = 0.02, respectively). CONCLUSIONS: ML-based immune phenotyping by spatial distribution of T cells in resected NSCLC is able to identify patients at greater risk of disease recurrence after surgical resection. LUADs with concurrent KEAP1 and STK11 mutations are enriched for altered and desert immune phenotypes.

Does chemotherapy improve health-related quality of life in advanced pancreatic cancer? A systematic review.

Chemotherapy is increasingly being used in advanced pancreatic cancer, but side-effects are common. The aim of this systematic review was to assess whether chemotherapy improves health-related quality of life (HRQoL), pain or cachexia. Thirty studies were reviewed. Four of 23 studies evaluating HRQoL, 7 of 24 studies evaluating pain and 0 of 8 studies evaluating cachexia found differences between treatment arms. Change in HRQoL from baseline was evaluated in 14 studies: five studies reported an improvement in at least one treatment arm; three a worsening and the remaining stable scores. Change in pain intensity from baseline was evaluated in eight studies, and improvement was observed in seven. Of the four studies reporting improved survival, three reported improved HRQoL or pain. In conclusion, chemotherapy can stabilize HRQoL and improve pain control. Effects on cachexia are hard to elucidate. Improved survival does not come at the expense of HRQoL or pain control.

Strategies for clinical implementation of TNM-Immunoscore in resected nonsmall-cell lung cancer.

Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates and appears highly promising as a supplement to the tumor-node-metastasis (TNM) classification of various tumors. In colorectal cancer, an international task force has initiated prospective multicenter studies aiming to implement TNM-Immunoscore (TNM-I) in a routine clinical setting. In breast cancer, recommendations for the evaluation of tumor-infiltrating lymphocytes (TILs) have been proposed by an international working group. Regardless of promising results, there are potential obstacles related to implementing TNM-I into the clinic. Diverse methods may be needed for different malignancies and even within each cancer entity. Nevertheless, a uniform approach across malignancies would be advantageous. In nonsmall-cell lung cancer (NSCLC), there are several previous reports indicating an apparent prognostic importance of TILs, but studies on TILs in a TNM-I setting are sparse and no general recommendations are made. However, recently published data is promising, evoking a realistic hope of a clinical useful NSCLC TNM-I. This review will focus on the TNM-I potential in NSCLC and propose strategies for clinical implementation of a TNM-I in resected NSCLC.

Vinorelbine and gemcitabine vs vinorelbine and carboplatin as first-line treatment of advanced NSCLC. A phase III randomised controlled trial by the Norwegian Lung Cancer Study Group.

BACKGROUND: Platinum-based doublet chemotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC), but earlier studies have suggested that non-platinum combinations are equally effective and better tolerated. We conducted a national, randomised study to compare a non-platinum with a platinum combination. METHODS: Eligible patients had stage IIIB/IV NSCLC and performance status (PS) 0-2. Patients received up to three cycles of vinorelbine 60 mg m(-2) p.o.+gemcitabine 1000 mg m(-2) i.v. day 1 and 8 (VG) or vinorelbine 60 mg m(-2) p.o. day 1 and 8+carboplatin area under the curve=5 (Calvert's formula) i.v. day 1 (VC). Patients ≥75 years received 75% of the dose. Endpoints were overall survival, health-related quality of life (HRQoL), toxicity, and the use of radiotherapy. RESULTS: We randomised 444 patients from September 2007 to April 2009. The median age was 65 years, 58% were men and 25% had PS 2. Median survival was VG: 6.3 months; VC: 7.0 months, P=0.802. Vinorelbine plus carboplatin patients had more grade III/IV nausea/vomiting (VG: 4%, VC: 12%, P=0.008) and grade IV neutropenia (VG: 7%, VC: 19%, P<0.001). Infections, HRQoL and the use of radiotherapy did not differ significantly between the treatment groups. CONCLUSION: The two regimens yielded similar overall survival. The VG combination had only a slightly better toxicity profile.

The length of consent documents in oncological trials is doubled in twenty years.

BACKGROUND: The aim of the study was to investigate whether the length of informed consent documents (ICDs) for oncological trials have increased from 1987 to 2007 and analyze the content of the ICDs. DESIGN: In total, 87 ICDs from oncological trials approved by the Regional Committee for Medical and Health Research Ethics (REC) in the central region of Norway from 1987 to 2007 were analyzed. A list of 17 basic (fundamental medical and ethical aspects) and 30 formal (juridical aspects, financing, insurance and storage of data) content components was constructed based upon international and REC guidelines for ICDs. The number of words and presence of components were registered for all ICDs. RESULTS: The mean length of the ICDs increased from 338 (range 276-464) words in 1987-1990 to 1087 words (range 399-2345) in 2005-2007. The number of components increased from nine to 25 during the same period. Basic components increased steadily from seven in 1987-1989 to 14 in 2005-2007 while the components concerning formalities increased substantially from two to 11. CONCLUSIONS: The increased length of the ICDs is explained by an increased complexity of the documents and especially more information about formalities. This development increasingly demands competent readers and might prohibit truly informed consents.

Prognostic significance of Ki-67/MIB-1 proliferation index in meningiomas.

Even though tumor grade, subtype, and extent of resection are strong prognostic factors in human meningiomas, the growth of this tumor is still unpredictable, and additional prognostic markers are needed. Thus, immunohistochemical determination of proliferative activity using the Ki-67 equivalent antibody MIB-1 has gained increased attention. However, the reported prognostic significance of this marker in meningiomas is not fully clarified. The aim of this study was to investigate the prognostic role of MIB-1 proliferation index (PI) in a series of meningiomas comprising 23 benign, 17 atypical, and 9 anaplastic tumors. MIB- 1 PI increased with increasing tumor grade and discriminated significantly benign from atypical and anaplastic meningiomas whereas no difference was found between the latter two grades. However, due to the considerable overlap of PI values between the various grades, one should be circumspect before using this criterion for tumor grading. Furthermore, MIB-1 PIs were significantly higher in recurrent tumors compared with non-recurrent and a reliable MIB-1 PI cut-off value of 10% was established. This value, however, cannot automatically be adapted by other laboratories and must be regarded just as a guideline. In conclusion, MIB-1 PI appears as an important prognostic factor and should be used in combination with traditional histological criteria for malignancy in order to identify meningiomas with increased risk of recurrence.

[The chemical working environment among car painters in Bergen]. / Kjemisk arbeidsmiljø blant billakkerere i Bergen.

Official guidelines have been prepared for the working environment in Norwegian spraylacquering garages, in order to reduce the incidence of symptoms and diseases related to exposure to organic solvents. 11 garages were visited to see if the guidelines were being followed. All the sprayers (n = 28) were examined by questionnaire about the occurrence of acute symptoms connected to the central nervous system, the skin, the eyes and the airways during work, and about their use of personal protective equipment. All the garages had specially ventilated rooms for the lacquering procedure, and all the workers used personal respiratory protective equipment. The sprayers did not report more acute symptoms than a control group of office workers employed in the same companies.