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.

Functional recovery after discharge in enhanced recovery video-assisted thoracoscopic lobectomy: a pilot prospective cohort study.

Little is known about functional recovery following patient discharge in an established enhanced recovery programme after video-assisted thoracoscopic lobectomy. We conducted a single-centre pilot prospective observational cohort study. We hypothesised that patients achieved early functional recovery after discharge. A total of 32 patients aged ≥ 18 years were enrolled. A digital device was used for objective activity measurements, and patient-reported outcomes were collected as subjective measurements. Primary outcomes were the difference in physical activity; sleep duration; pain; fatigue; and average quality of life scores between pre-operative baseline and 7 days following discharge. The secondary outcome was the reason for reduced daily activity during the first 7 days after discharge. Median (IQR [range]) length of stay was 3 (2-5 [1-13]) days. Up to post-discharge day 7, total, lower intensity and moderate-to-vigorous activities were lower than pre-operative activity (p < 0.001; p = 0.005 and p = 0.027, respectively). Numerical rating scale (0-10) pain scores increased postoperatively at rest (mean difference 1.2, p < 0.001) and during walking (mean difference 1.4, p < 0.001). Fatigue assessed by the Christensen Fatigue Scale (1-10) was also increased postoperatively (mean difference 1.7, p = 0.001). There was a reduction in quality of life scores, while sedentary activity and sleep duration were unchanged postoperatively. Dominant reasons for not recovering daily activity included fatigue in 43% and pain in 33% of patients. Despite compliance with an enhanced recovery programme with a median length of hospital stay of 3 days after video-assisted thoracoscopic lobectomy, functional recovery was not achieved within 7 days after hospital discharge. Reduction in postoperative pain and fatigue are important factors to enhance functional recovery.

A competing risk nomogram predicting cause-specific mortality in patients with lung adenosquamous carcinoma.

BACKGROUND: Adenosquamous carcinoma (ASC) is an uncommon histological subtype of lung cancer. The purpose of this study was to assess the cumulative incidences of lung cancer-specific mortality (LC-SM) and other cause-specific mortality (OCSM) in lung ASC patients, and construct a corresponding competing risk nomogram for LC-SM. METHODS: Data on 2705 patients with first primary lung ASC histologically diagnosed between 2004 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The cumulative incidence function (CIF) was utilized to calculate the 3-year and 5-year probabilities of LC-SM and OCSM, and a competing risk model was built. Based on the model, we developed a competing risk nomogram to predict the 3-year and 5-year cumulative probabilities of LC-SM and the corresponding concordance indexes (C-indexes) and calibration curves were derived to assess the model performance. To evaluate the clinical usefulness of the nomogram, decision curve analysis (DCA) was conducted. Furthermore, patients were categorized into three groups according to the tertile values of the nomogram-based scores, and their survival differences were assessed using CIF curves. RESULTS: The 3-year and 5-year cumulative mortalities were 49.6 and 55.8% for LC-SM and 8.2 and 11.8% for OCSM, respectively. In multivariate analysis, increasing age, male sex, no surgery, and advanced T, N and M stages were related to a significantly higher likelihood of LC-SM. The nomogram showed good calibration, and the 3-year and 5-year C-indexes for predicting the probabilities of LC-SM in the validation cohort were both 0.79, which were almost equal to those of the ten-fold cross validation. DCA demonstrated that using the nomogram gained more benefit when the threshold probabilities were set within the ranges of 0.24-0.89 and 0.25-0.91 for 3-year and 5-year LCSM, respectively. In both the training and validation cohorts, the high-risk group had the highest probabilities of LC-SM, followed by the medium-risk and low-risk groups (both P < 0.0001). CONCLUSIONS: The competing risk nomogram displayed excellent discrimination and calibration for predicting LC-SM. With the aid of this individualized predictive tool, clinicians can more expediently devise appropriate treatment protocols and follow-up schedules.

Characteristics of 252 patients with bronchopulmonary neuroendocrine tumours treated at the Copenhagen NET Centre of Excellence.

BACKGROUND: Bronchopulmonary neuroendocrine tumours are divided into typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung cancer (SCLC). AIM: To thoroughly describe a cohort of 252 patients with TC, AC and LCNEC (SCLC excluded). MATERIAL AND METHODS: Collection of data from 252 patients referred to and treated at Rigshospitalet 2008-2016. Data was collected from electronic patient files and our prospective NET database. Statistics were performed in SPSS. RESULTS: 162 (64%) had TC, 29 (12%) had AC and 61 (24%) had LCNEC. Median age at diagnosis was 69 years (range: 19-89) with no difference between genders. Thoraco-abdominal CT was performed in all patients at diagnosis. FDG-PET/CT was performed in 207 (82%) at diagnosis and was positive in 95% of the entire cohort, with no difference between tumour types. Synaptophysin was positive in 98%, chromogranin A in 92% and CD56 in 97%. Mean Ki67 index was 5% in TC, 16% in AC and 69% in LCNEC (p < 0.001). Metastatic disease was found in 4% of TC, 27% of AC and 58% of LCNEC at time of initial diagnosis (p < 0.001). In total 179 patients (71%) underwent surgical resection; TC: 87%, AC: 72% and LCNEC: 28% (p < 0.001). Of the resected patients, 11 (6%) had recurrence. Five-year survival rate was 88% for TC, 63% for AC and 20% for LCNEC. CONCLUSION: In this comprehensive study of a cohort of 252 patients, one of the largest until date, with TC, AC and LCNEC, the gender distribution showed female predominance with 68%. FDG-PET/CT was positive in 95% of the patients independent of tumour type, which confirms that FDG-PET/CT should be a part of the preoperative work-up for TC, AC and LCNEC. Tumour type was the single most potent independent prognostic factor.

Persistent postsurgical pain after video-assisted thoracic surgery--an observational study.

BACKGROUND: The risk of persistent postsurgical pain (PPP) and subsequent pain-related functional impairment may potentially be reduced by video-assisted thoracic surgery (VATS) compared to thoracotomy. The aim of the study was therefore to assess in detail the incidence and consequences on activities of daily living of PPP after VATS. METHODS: Using a prospective observational design, 47 patients undergoing VATS completed both preoperative, early postoperative and 3 months follow-up. Preoperative pain, pain characteristics, psychological factors, pain-related functional impairment and quantitative sensory testing (QST) including nociceptive thresholds were compared with postoperative data. RESULTS: Only five (11%) patients developed PPP with NRS > 3 originating from the surgical area. However, about 30% of patients still reported some pain-related functional impairment from the surgical area within four well-defined domains of everyday activities. Psychological and sensory thermal tests did not predict persistent postoperative pain, except preoperative pin-prick sensitivity was higher in patients with PPP. Postoperative pain 7 days after surgery was significantly higher in PPP patients. Preoperative pain originating from remote areas did not predict PPP. CONCLUSION: The incidence of PPP, nerve damage (based on QST) and pain-related functional impairment following VATS was lower than reported following thoracotomy. No psychological or other factors predicted PPP. These findings call for further large-scale studies to support VATS to decrease PPP.

Quantitative sensory testing of persistent pain after video-assisted thoracic surgery lobectomy.

BACKGROUND: Video-assisted thoracic surgery (VATS) lobectomy may potentially reduce the risk of post-thoracotomy pain syndrome (PTPS). However, it may still carry a risk of intraoperative nerve damage and thereby development of PTPS. Thus, our aim was to present a detailed long-term neurophysiological characterization of PTPS after VATS. METHODS: Quantitative sensory testing, using thermal and mechanical stimuli, was performed in 13 PTPS patients and 35 pain-free patients recruited 33 months after VATS lobectomy. RESULTS: When comparing the operated side with the control side in PTPS patients, increased thresholds of tactile and warmth detection were observed, while in pain-free patients, increased thresholds of warmth detection, cool detection, and heat pain were demonstrated. At the anterior porthole, pain-free patients displayed increased threshold to thermal detection when compared with the control side. Only side-to-side difference for tactile detection threshold was increased in PTPS patients compared with pain-free patients. Assessment of central sensitization showed no significant differences within or between PTPS and pain-free patients nor did group comparison of area of hypo- and hyperaesthesia to cool. Anxiety and depression scores (HADS) were higher in PTPS patients, but the area of hyper- and hypoaesthesia did not differ significantly between HADS groups. CONCLUSIONS: Increased sensory thresholds suggest nerve injury to be present on the operated side in both PTPS and pain-free patients. However, no significant quantitative differences between PTPS and pain-free patients could be found, implicating the presence of factors other than intercostal nerve injury as important for development of PTPS after VATS lobectomy.

[Recurrence and survival after conventional low anterior resection for rectal cancer]. / Recidiv og overlevelse efter konventionel lav anterior resektion for cancer recti.

INTRODUCTION: The aim of the study was to evaluate the incidence of recurrence of local cancer, distant metastases and survival after conventional low anterior resection for cure in patients with rectal carcinoma, on the basis of the poor prognosis after colorectal cancer in Denmark. MATERIAL AND METHODS: Consecutive patients operated on in the nine Danish departments of surgical gastroenterology in 1992-1993. Retrospective collection of data on recurrence of local cancer, distant metastases, and over-all survival at the end of 1996. RESULTS: Of 268 patients, 77 (29%) developed recurrent local cancer and/or distant metastases. Forty-eight (18%) had local recurrence with a cumulative 5-year rate of 39%. Distant metastases were seen in 54 (20%). The local recurrence rate increased with increasing Dukes' tumour stage and was higher after operation by a non-specialist (30%) than by a consultant, another specialist, or a surgeon under training and supervised by a consultant (15-17%) (p = 0.04). Multiple regression showed that the recurrence rate was independent of tumour localisation, blood loss, transfusion, anastomotic leakage, and status of the surgeon. The cumulative crude 5-year survival was 50% and independent of the status of the surgeon. DISCUSSION: Our relatively high local recurrence rate and the results in the literature after total mesorectal excision (TME) indicate that the conventional technique should be replaced by TME, which has become the recommended method in recent years. Furthermore, we propose a changed strategy in the treatment of rectal cancer. The patients should be treated in fewer departments with established teams of rectal cancer specialists taking part in all operations for rectal cancer.

New species of Lentaria (Fungi: Aphyllophorales): redescription and mating systems of L. surculus and L. byssiseda.

The following names are proposed for species of Lentaria new to science: L. boletosporioides from New Zealand with stout basidiomata and boletoid basidiospores; L. caribbeana from Caribbean islands and circum-Caribbean landmasses, with large basidiomata and large basidiospores; L. glaucosiccescens from New Zealand, with basidiomata turning grey-green upon drying; and L. rionegrensis from Argentina, with densely branched, ruddy basidiomata. Lentaria javanica nom. nov. is proposed to substitute for Clavaria compressa, a later homonym. Basidiospore statistics indicate infraspecific differentiation within L. surculus and two morphological variants are described. Lentaria surculus and L. byssiseda exhibit tetrapolar mating systems, and the two species are sexually interincompatible.

[Cystic fibrosis and chronic Pseudomonas aeruginosa infection. Possibilities for immunologic prophylaxis and therapy]. / Cystisk fibrose og kronisk Pseudomonas aeruginosa. Muligheder for immunprofylakse og -terapi.

Cystic fibrosis is an autosomal recessive disease, characterised by chronic pulmonary infections, pancreatic insufficiency and increased electrolyte content of sweat. Cystic fibrosis is diagnosed in one out of 4761 children below the age of 15 years. Pulmonary infection was previously caused by Staphylococcus aureus, but after the introduction of penicillin, the mortality was reduced from 61% to 20% within the first five years of life. Today chronic pulmonary infection is primarily caused by Pseudomonas aeruginosa. P. aeruginosa infection produces an immunologically conditioned destruction of the pulmonary tissue, leading to fatal bronchiectasis. P. aeruginosa develops resistance against most antibiotics and chemotherapeutic agents except colistin. Immunological aspects concerning active and passive immunisation are discussed in the article. Until today no useable vaccine has been found, but several candidates are subjects of research.

Differential effect of extracellular calcium on the Na(+)-K+ pump activity in intact polymorphonuclear leucocytes and erythrocytes.

The effect of extracellular calcium on the Na(+)-K+ pump activity in human polymorphonuclear leucocytes and erythrocytes was studied and compared with the activity in mixed peritoneal leucocytes from rats. While there was maximal decrease in the pump activity (25-30%) of leucocytes from both rat and human by calcium 0.6 mM, a concentration of 0.1 mM caused a substantial decrease indicating a high sensitivity for extracellular calcium. In contrast, calcium had no effect on the pump activity in erythrocytes. The effect of calcium on the pump activity in leucocytes may be due to regulation of the influx of sodium across the plasma membrane, since in human leucocytes calcium had no effect on the pump activity if the cells were loaded with sodium.