Spatial proteomic profiling of tumor and stromal compartments in non-small-cell lung cancer identifies signatures associated with overall survival.

Objectives: Non-small-cell lung carcinoma (NSCLC) is the most prevalent and lethal form of lung cancer. The need for biomarker-informed stratification of targeted therapies has underpinned the need to uncover the underlying properties of the tumor microenvironment (TME) through high-plex quantitative assays. Methods: In this study, we profiled resected NSCLC tissues from 102 patients by targeted spatial proteomics of 78 proteins across tumor, immune activation, immune cell typing, immune-oncology, drug targets, cell death and PI3K/AKT modules to identify the tumor and stromal signatures associated with overall survival (OS). Results: Survival analysis revealed that stromal CD56 (HR = 0.384, P = 0.06) and tumoral TIM3 (HR = 0.703, P = 0.05) were associated with better survival in univariate Cox models. In contrast, after adjusting for stage, BCLXL (HR = 2.093, P = 0.02) and cleaved caspase 9 (HR = 1.575, P = 0.1) negatively influenced survival. Delta testing indicated the protective effect of TIM-3 (HR = 0.614, P = 0.04) on OS. In multivariate analysis, CD56 (HR = 0.172, P = 0.001) was associated with better survival in the stroma, while B7.H3 (HR = 1.72, P = 0.008) was linked to poorer survival in the tumor. Conclusions: Deciphering the TME using high-plex spatially resolved methods is giving us new insights into compartmentalised tumor and stromal protein signatures associated with clinical endpoints in NSCLC.

Characterisation of circulating tumor-associated and immune cells in patients with advanced-stage non-small cell lung cancer.

Objectives: Globally, non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer and the leading cause of cancer-related deaths. Tumor-associated circulating cells in NSCLC can have a wide variety of morphological and phenotypic characteristics, including epithelial, immunological or hybrid subtypes. The distinctive characteristics and potential clinical significance of these cells in patients with NSCLC are explored in this study. Methods: We utilised a spiral microfluidic device to enrich large cells and cell aggregates from the peripheral blood samples of NSCLC patients. These cells were characterised through high-resolution immunofluorescent imaging and statistical analysis, correlating findings with clinical information from our patient cohort. Results: We have identified varied populations of heterotypic circulating tumor cell clusters with differing immune cell composition that included a distinct class of atypical tumor-associated macrophages that exhibits unique morphology and cell size. This subtype's prevalence is positively correlated with the tumor stage, progression and metastasis. Conclusions: Our study reveals a heterogeneous landscape of circulating tumor cells and their clusters, underscoring the complexity of NSCLC pathobiology. The identification of a unique subtype of atypical tumor-associatedmacrophages that simultaneously express both tumor and immune markers and whose presence correlates with late disease stages, poor clinical outcomes and metastatic risk infers  the potential of these cells as biomarkers for NSCLC staging and prognosis. Future studies should focus on the role of these cells in the tumor microenvironment and their potential as therapeutic targets. Additionally, longitudinal studies tracking these cell types through disease progression could provide further insights into their roles in NSCLC evolution and response to treatment.

Lorlatinib After Alectinib-Induced Pneumonitis: A Case Report.

ALK gene rearrangements are detected in approximately 3% to 5% of NSCLC. ALK tyrosine kinase inhibitors, such as third-generation lorlatinib, have exhibited remarkable efficacy in ALK-rearranged NSCLC; however, they have been associated with a low incidence of treatment-limiting and potentially fatal drug-induced interstitial lung disease (ILD). There is concern that this may represent a class effect, a theory that is supported by a number of case reports. Because of clinical trial exclusion criteria, there are limited prospective data to guide decision-making after ALK tyrosine kinase inhibitors-induced ILD. A systematic review of the literature was conducted and only identified four reported cases of lorlatinib safety in this context. Here, we report the successful sequencing of lorlatinib in a patient who discontinued alectinib secondary to grade 3 drug-induced ILD.

The prognostic value of the derived neutrophil-to-lymphocyte ratio (dNLR) in patients treated with immune checkpoint inhibitors.

BACKGROUND: The (derived) neutrophil-to-lymphocyte ratio (dNLR) is a potential predictive biomarker in the era of checkpoint inhibitors (CPI). An elevated dNLR is associated with worse outcomes across several malignancies. However, there is no clearly defined cut-off in the clinical setting. AIM: To compare outcomes in patients prescribed CPI with a baseline dNLR0 > 3 and dNLR0 ≤ 3. The dNLR6 was measured 6 weeks later to determine its impact on patient overall survival (OS). METHODS: Prospectively maintained pharmacy databases in a regional cancer centre were interrogated for patients who were prescribed CPI in the advanced setting between January 2017 and May 2020. RESULTS: There were 121 patients with advanced cancer and a median age of 68 (range 30 to 88) years. Forty-four percent (n = 53) received prior systemic therapy. Patients with an initial dNLR0 > 3 when compared with a dNLR0 ≤ 3 had significantly shorter median progression-free survival (PFS), 3 vs. 14 months (p = 0.001) and median OS, 6.4 vs. 30.2 months (p = 0.001). Patients with an initial dNLR0 > 3 and increased dNLR at 6 weeks (dNLR6) had significantly reduced median PFS (3.5 vs. 14.7 months, p = 0.03) and OS (5.7 vs. 16.3, p = 0.03) when compared with those whose dNLR decreased. In the dNLR0 ≤ 3 cohort, any increased dNLR when compared with decreased dNLR after 6 weeks of CPI had significantly reduced PFS (8.4 months vs. NR, p = 0.01) and OS (24.2 months vs. NR, p = 0.02). CONCLUSIONS: Lower pre-CPI treatment dNLR is associated with improved OS. A decrease in dNLR during treatment confers improved OS.

Network autonomic analysis of post-acute sequelae of COVID-19 and postural tachycardia syndrome.

BACKGROUND: The autonomic nervous system (ANS) is a complex network where sympathetic and parasympathetic domains interact inside and outside of the network. Correlation-based network analysis (NA) is a novel approach enabling the quantification of these interactions. The aim of this study is to assess the applicability of NA to assess relationships between autonomic, sensory, respiratory, cerebrovascular, and inflammatory markers on post-acute sequela of COVID-19 (PASC) and postural tachycardia syndrome (POTS). METHODS: In this retrospective study, datasets from PASC (n = 15), POTS (n = 15), and matched controls (n = 11) were analyzed. Networks were constructed from surveys (autonomic and sensory), autonomic tests (deep breathing, Valsalva maneuver, tilt, and sudomotor test) results using heart rate, blood pressure, cerebral blood flow velocity (CBFv), capnography, skin biopsies for assessment of small fiber neuropathy (SFN), and various inflammatory markers. Networks were characterized by clusters and centrality metrics. RESULTS: Standard analysis showed widespread abnormalities including reduced orthostatic CBFv in 100%/88% (PASC/POTS), SFN 77%/88%, mild-to-moderate dysautonomia 100%/100%, hypocapnia 87%/100%, and elevated inflammatory markers. NA showed different signatures for both disorders with centrality metrics of vascular and inflammatory variables playing prominent roles in differentiating PASC from POTS. CONCLUSIONS: NA is suitable for a relationship analysis between autonomic and nonautonomic components. Our preliminary analyses indicate that NA can expand the value of autonomic testing and provide new insight into the functioning of the ANS and related systems in complex disease processes such as PASC and POTS.

Prognostic factors influencing survival following re-resection for isocitrate dehydrogenase (IDH) -wildtype glioblastoma multiforme - Data from a national neuro-oncology registry.

The role of surgical resection in recurrent Glioblastoma Multiforme (GBM) remains unclear. We aimed to investigate survival outcomes and associated prognostic factors in patients undergoing surgical re-resection for recurrent IDH-wildtype GBM in a national neuro-oncology center. We evaluated all patients who underwent re-resection for recurrent GBM following adjuvant treatment between 2015 and 2018. 32 patients were eligible for inclusion. 19 (59%) were male,median age at re-resection was 53. Median time from initial surgery to re-resection was 13.5 months. Median overall survival (OS) was 28.6 months from initial surgery and 9.5 months from re-resection. MGMT methylation was significantly associated with improved OS from initial surgery, 40 months versus 19.1 months, (p = 0.004), and from re-resection, 9.47 months versus 6.93 months, (p = 0.028). A late re-resection was associated with improved OS compared to an early re-resection, 44.1 months versus 15.7 months, (p = 0.002). There was a trend for improved outcomes in younger patients, median OS from initial surgery 44.1 months for <53 years compared to 21.7 months for patients ≥53, (p = 0.099). Higher Karnofsky Performance Status (KPS) at re-resection was associated with improved median OS, 9.5 months versus 4.1 months for KPS ≥70 and <70 respectively, (p = 0.013). Furthermore, there was a trend for improved OS with greater extent of re-resection, however this did not reach statistical significance, possibly due to small sample size. Re-resection for recurrent GBM was associated with improved OS in those with good performance status and could be considered in carefully selected cases.

Lack of familiarity with genetic testing among patients in Ireland with Cancer.

BACKGROUND: Cancer gene panel testing is available in Ireland. The need for a clear strategy to deal with patient information generated from tumour genomic testing is recognised as a challenge in the National Cancer Strategy. However, the public's attitude and opinions regarding these results is not known in Ireland. AIMS: This prospective questionnaire study assessed the knowledge and opinions of patients in a national oncology centre, surrounding cancer gene panel testing. METHODS: An anonymised modified validated questionnaire was completed by volunteering patients in the medical oncology department. It comprised 14 questions which assessed patient's familiarity, intention, benefits and concerns associated with tumour genetic testing using a four-point Likert scale. Patients recorded their primary cancer diagnosis and family cancer history. RESULTS: Eighty-four patients completed the questionnaire with 77 (92%) patients declaring their primary cancer diagnosis. The median age was 56 (range 26 to 83) years. Overall, 42% (n = 35) of oncology patients were familiar/somewhat familiar with testing and 90% (n = 76) stated they would avail of genetic testing if available. Patients with breast cancer were no more likely to avail of genetic testing when compared with the non-breast cancer cohort (n = 21 vs. 56, p = 0.58) though they identified concerns with potential discrimination. CONCLUSION: This is the first prospective Irish study to assess opinions surrounding cancer gene results. Addressing patient's lack of information as regards genetic testing is the first step in establishing a national cancer genetics testing programme in Ireland.

Pain Neurology.

Pain is often the initial complaint for which patients seek medical care, presenting both a diagnostic and therapeutic challenge to the primary care provider. The appreciation of pain is not merely the result of abnormal sensory stimulation causing an unpleasant sensation but rather a combination of the recognition of the somatic discomfort in association with an emotional response to that discomfort. The perception of pain and the extent of distress and disability can vary depending on previous experience, cultural background, situational factors, and comorbid psychiatric disease. Though acute pain is usually the result of tissue damage, this is not always the case, as evidenced by primary headache disorders. Chronic pain may be the result of an injury, irreversible underlying disease, or clinical conditions such as fibromyalgia for which the mechanism remains unclear. Treatment of the underlying cause will usually effect a resolution or improvement in the pain, but when the discomfort persists, a consultation with a neurologist or pain management specialist should be considered.

Lung cancer in young patients: tumour characteristics and treatment in an Irish population.

BACKGROUND: Lung cancer is the leading cause of cancer death in both sexes in Ireland. Studies suggest that lung cancer in younger patients has distinct characteristics. The aim of this study is to define the characteristics of lung cancer in patients 55-year-old or younger in an Irish population. METHODS: Data was collected retrospectively from local medical records and the hospital electronic database regarding all patients diagnosed with lung cancer aged 55-year-old and younger, from 2010-2016. Information regarding patient demographics, smoking status, tumour histology, molecular analysis, stage and location, diagnostic modality and initial treatment choice was collected. In all cases the diagnosis of lung cancer was confirmed at the regional lung cancer multidisciplinary team (MDT) meeting. RESULTS: In total, 8% (n=130) of all cases of lung cancer diagnosed from 2010 to 2016 in our center occurred in patients aged 55 years old or younger; 83% (n=108) were 45 to 55-year-old, 15% (n=19) were 35 to 44-year-old and 2% (n=3) were younger than 35-year-old; 88% (n=115) of patients reported a smoking history. There was a female preponderance (58%, n=76), higher rates of NSCLC non-squamous subtype (53%, n=69) and an upper lobe predominance (42%, n=54); 53% (n=68) of patients had IV or extensive disease at presentation. Epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and Kirsten rat sarcoma oncogene (KRAS) mutation rates were 9% (n=4) and 3% (n=1) and 80% (n=4) respectively. CONCLUSIONS: Lung cancer in younger patients has distinct characteristics. This study suggests a female preponderance, high smoking rates and a predilection for the upper lobes. Further large-scale multicenter studies are required to verify these results and to clarify the responsible mechanisms.

Value of Patient-Directed Brain Magnetic Resonance Imaging Scan with a Diagnosis of Migraine.

BACKGROUND: The objective of this study was to determine whether a brain magnetic resonance imaging (MRI) scan in patients with a diagnosis of migraine, who insist on the performance of imaging, is of more benefit in detecting clinically significant unsuspected structural abnormalities than would be expected by chance. METHODS: This prospective, observational, single-center study was performed from January 1, 2010 to December 31, 2012 and included 100 subjects with a diagnosis of migraine and normal results on neurologic examination. A brain MRI scan was performed on all patients, solely at their request, to detect an unsuspected clinically significant structural lesion. RESULTS: Of the 100 patients, 86 were female, and the average age was 31.5 years. Forty-five patients experienced migraine without aura, 41 chronic migraine, and 14 migraine with aura. All of the patients had normal results on neurologic examination. The duration of headaches ranged from 4 months to 40 years. In all, 82 of the MRI scans showed normal results, and 17 revealed clinically insignificant abnormalities. One MRI in a patient with chronic migraine without aura revealed a meningioma that subsequently required surgery and radiation therapy. The 1% prevalence of tumor in this study was then compared with 2 large cohorts of MRI abnormalities in the general asymptomatic population, in which tumor was found in 35 out of 3000. Fisher's exact test was used to compare the prevalence of tumor in the study population with the combined cohorts, and there was no statistical difference between these rates (P > .99). CONCLUSIONS: Brain MRI obtained at the specific request of patients with a diagnosis of migraine in the presence of normal neurologic examination results has a yield that is equivalent to that of the general asymptomatic population. Patients do not seem to have more insight than the examining clinician with regard to detecting underlying structural abnormalities, and brain MRI should not performed as part of the routine evaluation of migraine without a clear clinical indication.

Hypnic headache secondary to haemangioblastoma of the cerebellum.

We report a case of secondary hypnic headache in a patient with a haemangioblastoma of the cerebellum. The number of secondary cases is steadily increasing in the medical literature and magnetic resonance imaging of the brain should be considered mandatory after arriving at a presumptive diagnosis.

Segmentation of nodules on chest computed tomography for growth assessment.

Several segmentation methods to evaluate growth of small isolated pulmonary nodules on chest computed tomography (CT) are presented. The segmentation methods are based on adaptively thresholding attenuation levels and use measures of nodule shape. The segmentation methods were first tested on a realistic chest phantom to evaluate their performance with respect to specific nodule characteristics. The segmentation methods were also tested on sequential CT scans of patients. The methods' estimation of nodule growth were compared to the volume change calculated by a chest radiologist. The best method segmented nodules on average 43% smaller or larger than the actual nodule when errors were computed across all nodule variations on the phantom. Some methods achieved smaller errors when examined with respect to certain nodule properties. In particular, on the phantom individual methods segmented solid nodules to within 23% of their actual size and nodules with 60.7 mm3 volumes to within 14%. On the clinical data, none of the methods examined showed a statistically significant difference in growth estimation from the radiologist.