End-of-Life Care in the Last Three Months before Death in Older Patients with Cancer in Belgium: A Large Retrospective Cohort Study Using Data Linkage.

This study aims to describe end-of-life (EOL) care in older patients with cancer and investigate the association between geriatric assessment (GA) results and specialized palliative care (SPC) use. Older patients with a new cancer diagnosis (2009-2015) originally included in a previous multicentric study were selected if they died before the end of follow-up (2019). At the time of cancer diagnosis, patients underwent geriatric screening with Geriatric 8 (G8) followed by GA in case of a G8 score ≤14/17. These data were linked to the cancer registry and healthcare reimbursement data for follow-up. EOL care was assessed in the last three months before death, and associations were analyzed using logistic regression. A total of 3546 deceased older patients with cancer with a median age of 79 years at diagnosis were included. Breast, colon, and lung cancer were the most common diagnoses. In the last three months of life, 76.3% were hospitalized, 49.1% had an emergency department visit, and 43.5% received SPC. In total, 55.0% died in the hospital (38.5% in a non-palliative care unit and 16.4% in a palliative care unit). In multivariable analyses, functional and cognitive impairment at cancer diagnosis was associated with less SPC. Further research on optimizing EOL healthcare utilization and broadening access to SPC is needed.

Long-term health-care utilisation in older patients with cancer and the association with the Geriatric 8 screening tool: a retrospective analysis using linked clinical and population-based data in Belgium.

BACKGROUND: Little evidence is available on the long-term health-care utilisation of older patients with cancer and whether this is associated with geriatric screening results. We aimed to evaluate long-term health-care utilisation among older patients after cancer diagnosis and the association with baseline Geriatric 8 (G8) screening results. METHODS: For this retrospective analysis, we included data from three cohort studies for patients (aged ≥70 years) with a new cancer diagnosis who underwent G8 screening between Oct 19, 2009 and Feb 27, 2015, and who survived more than 3 months after G8 screening. The clinical data were linked to cancer registry and health-care reimbursement data for long-term follow-up. The occurrence of outcomes (inpatient hospital admissions, emergency department visits, use of intensive care, contacts with general practitioner [GP], contacts with a specialist, use of home care, and nursing home admissions) was assessed in the 3 years after G8 screening. We assessed the association between outcomes and baseline G8 score (normal score [>14] or abnormal [≤14]) using adjusted rate ratios (aRRs) calculated from Poisson regression and using cumulative incidence calculated as a time-to-event analysis with the Kaplan-Meier method. FINDINGS: 7556 patients had a new cancer diagnosis, of whom 6391 patients (median age 77 years [IQR 74-82]) met inclusion criteria and were included. 4110 (64·3%) of 6391 patients had an abnormal baseline G8 score (≤14 of 17 points). In the first 3 months after G8 screening, health-care utilisation peaked and then decreased over time, with the exception of GP contacts and home care days, which remained high throughout the 3-year follow-up period. Compared with patients with a normal baseline G8 score, patients with an abnormal baseline G8 score had more hospital admissions (aRR 1·20 [95% CI 1·15-1·25]; p<0·0001), hospital days (1·66 [1·64-1·68]; p<0·0001), emergency department visits (1·42 [1·34-1·52]; p<0·0001), intensive care days (1·49 [1·39-1·60]; p<0·0001), general practitioner contacts (1·19 [1·17-1·20]; p<0·0001), home care days (1·59 [1·58-1·60]; p<0·0001), and nursing home admissions (16·7% vs 3·1%; p<0·0001) in the 3-year follow-up period. At 3 years, of the 2281 patients with a normal baseline G8 score, 1421 (62·3%) continued to live at home independently and 503 (22·0%) had died. Of the 4110 patients with an abnormal baseline G8 score, 1057 (25·7%) continued to live at home independently and 2191 (53·3%) had died. INTERPRETATION: An abnormal G8 score at cancer diagnosis was associated with increased health-care utilisation in the subsequent 3 years among patients who survived longer than 3 months. FUNDING: Stand up to Cancer, the Flemish Cancer Society.

Linking clinical and population-based data in older patients with cancer in Belgium: Feasibility and clinical outcomes.

INTRODUCTION: Geriatric screening and geriatric assessment (GS/GA) have proven their benefits in the care for older patients with cancer. However, less is known about the predictive value of GS/GA for outcomes. To research this, clinical data on GS/GA can be enriched with population-based data. In this article we describe the methods and feasibility of data linkage, and first clinical outcomes (GS/GA results and overall survival). MATERIALS AND METHODS: A large cohort study consisting of patients aged ≥70 years with a new cancer diagnosis was established using linked data from clinical and population-based databases. Clinical data were derived from a previous prospective study where older patients with cancer were screened with G8, followed by GA in case of an abnormal result (GS/GA study; 2009-2015). These data were linked to cancer registration data from the Belgian Cancer Registry (BCR), reimbursement data of the health insurance companies (InterMutualistic Agency, IMA), and hospital discharge data (Technical Cell, TCT). Cox regression analyses were conducted to evaluate the prognostic value of the G8 geriatric screening tool. RESULTS: Of the 8067 eligible patients with a new cancer diagnosis, linkage of data from the GS/GA study and data from the BCR was successful for 93.7%, resulting in a cohort of 7556 patients available for the current analysis. Further linkage with the IMA and TCT database resulted in a cohort of 7314 patients (96.8%). Based on G8 geriatric screening, 67.9% of the patients had a geriatric risk profile. Malnutrition and functional dependence were the most common GA-identified risk factors. An abnormal baseline G8 score (≤14/17) was associated with lower overall survival (adjusted HR [aHR] = 1.62 [1.50-1.75], p < 0.001). DISCUSSION: Linking clinical and population-based databases for older patients with cancer has shown to be feasible. The GS/GA results at cancer diagnosis demonstrate the vulnerability of this population and the G8 score showed prognostic value for overall survival. The established cohort of almost 8000 patients with long-term follow-up will serve as a basis in the future for detailed analyses on long-term outcomes beyond survival.

Unplanned hospitalizations in older patients with cancer: Occurrence and predictive factors.

BACKGROUND: This study aims to investigate the occurrence of unplanned hospitalizations in older patients with cancer and to determine predictive factors. METHODS: A prospective Belgian multicentre (n = 22), observational cohort study was performed. Patients ≥70 years with a malignant tumor were included. Patients underwent G8 screening followed by geriatric assessment (GA) if abnormal at baseline and were followed for unplanned hospitalizations at approximately three months. Uni- and multivariable regression models were performed to determine predictive factors associated with unplanned hospitalizations in older patients with an abnormal G8. RESULTS: In total, 7763 patients were included in the current analysis of which 2409 (31%) patients with a normal G8 score and 5354 (69%) with an abnormal G8 score. Patients with an abnormal G8 were hospitalized more frequently than patients with a normal G8 (22.9% versus 12.4%; p < 0.0001). Reasons for unplanned hospitalizations were most frequently cancer related (25.7%) or cancer therapy related (28%). In multivariable analysis, predictive factors for unplanned hospitalizations in older patients with cancer and an abnormal G8 were female gender, absence of surgery, chemotherapy, ADL dependency, malnutrition and presence of comorbidities. CONCLUSION: Older patients with cancer and an abnormal G8 screening present a higher risk (23%) for unplanned hospitalizations. Predictive factors for these patients were identified and include not only patient and treatment related factors but also GA related factors.

The prognostic value of patient-reported Health-Related Quality of Life and Geriatric Assessment in predicting early death in 6769 older (≥70 years) patients with different cancer tumors.

OBJECTIVES: We aimed to determine the prognostic value of baseline Health-Related Quality Of Life (HRQOL) and geriatric assessment (GA) to predict three-month mortality in older patients with cancer undergoing treatment. METHODS: Logistic regressions analysed HRQOL, as measured with the EORTC Global Health Status (GHS) scale, and geriatric information prognostic for early mortality controlling for oncology variables. The assessment was established with the odds ratio (OR), 95% confidence interval (CI) and level of significance set at p < 0.05. Discriminative power was evaluated with area under the curve (AUC). RESULTS: In total, 6769 patients were included in the study, of whom 1259 (18.60%) died at three months. Our model showed higher odds of early death for patients with lower HRQOL (GHS, OR 0.98, 95% CI 0.98-0.99; p < 0.001), a geriatric risk profile (G8 Screening Tool, 1.94, 1.14-3.29; p = 0.014), cognitive decline (Mini Mental State Examination, 1.41, 1.15-1.72; p = 0.001), being at risk for malnutrition (Mini Nutritional Assessment-Short Form, 1.54, 1.21-1.98; p = 0.001), fatigue (Visual Analogue Scale for Fatigue, 1.45, 1.16-1.82; p = 0.012) and comorbidities (Charlson Comorbidity index, 1.23, 1.02-1.49; p = 0.033). Additionally, older age, poor ECOG PS and being male increased the odds of early death, although the magnitude differed depending on tumor site and stage, and treatment (all p < 0.05). Predictive accuracy increased with 3.7% when including HRQOL and GA in the model. CONCLUSION: The results suggest that, in addition to traditional clinical measures, HRQOL and GA provide additional prognostic information for early death, but the odds differ by patient and tumor characteristics.

c-MET as a Potential Resistance Mechanism to Everolimus in Breast Cancer: From a Case Report to Patient Cohort Analysis.

BACKGROUND: We describe in a patient with breast cancer the change in c-MET expression during everolimus treatment, opening a better understanding of the resistance to everolimus and a role for cabozantinib. OBJECTIVE: The objective of this study was to evaluate c-MET as a potential predictive biomarker for everolimus efficacy in breast cancer. METHODS: We first selected a patient with breast cancer with a long-lasting response to everolimus and retrospectively profiled biopsies that were taken before everolimus initiation (Biopsy 1) and at progression on everolimus (Biopsy 2) using amplicon sequencing and immunohistochemistry. We then retrospectively evaluated c-MET expression in a cohort of patients with breast cancer treated with everolimus. RESULTS: While not expressed in Biopsy 1, c-MET was highly expressed in Biopsy 2, suggesting a role for c-MET in breast cancer progression. Cabozantinib resulted in a rapid radiological response in this patient. Twenty-nine patients were included (12 c-MET-positive and 17 c-MET-negative patients) in the second part of the study. Baseline c-MET expression was associated with higher tumor grade, higher frequency of visceral metastases, and lower endocrine sensitivity. The c-MET-positive patients presented with a shorter progression-free survival (6.1 vs 10.5 months, respectively; p = 0.002) and a lower response rate (0% vs 12%) to everolimus, compared with c-MET-negative patients. CONCLUSIONS: c-MET could play a role in the resistance to everolimus and its inhibition should be evaluated in breast cancer.

Isolated adrenocorticotropic hormone (ACTH) deficiency and Guillain-Barré syndrome occurring in a patient treated with nivolumab.

The increased use of immune checkpoint inhibitors (ICIs) has led to the observation of a variety of immune-related adverse events (irAEs). These irAEs occur usually within the first months after ICIs onset and can involve theorically all organs. We describe two rare irAEs occurring in a 70-year-old caucasian man who was treated with nivolumab for an advanced urothelial cancer of the left kidney. He developed an isolated adrenocorticotropic hormone deficiency that was diagnosed at week 19 and a neurological complication that appeared at week 79 and initially confounded with a lumbar spinal stenosis. Diagnosis of Guillain-Barré syndrome was finally confirmed with the complete resolution of symptoms after 5 days of intravenous immunoglobulin and corticosteroids. We highlight the importance of quickly recognising these potential life-threatening irAEs such as cortisol insufficiency and neurologic adverse events whose initially presentation could be non-specific.

Health related quality of life in older patients with solid tumors and prognostic factors for decline.

OBJECTIVES: This study aims to investigate health-related quality of life (HRQOL) at baseline and at follow-up in older patients with cancer and to determine prognostic factors for HRQOL decline. METHODS: A prospective Belgian multicentre (n = 22) study was performed. Patients ≥70 years with a malignant tumor and abnormal G8 (≤14/17) screening tool were included. Patients underwent geriatric assessment (GA) and HRQOL evaluation with follow up at three months. Uni- and multivariate regression models were performed to determine factors associated (p < .05) with baseline HRQOL and HRQOL decline at follow-up. RESULTS: Results reflect data collected from 3673 patients. A multivariate analysis showed that younger patients, and those with poor Eastern Cooperative Oncology Group - Performance Status (ECOG-PS), specific tumor types (gastrointestinal, gynaecological and thorax) and higher stage had lower baseline HRQOL. In addition worse functional status and presence of pain, fatigue, depression and malnutrition were associated with lower baseline HRQOL. During treatment (n = 2972), improvement in HRQOL was observed in 1037 patients (35%) and a decline in 838 patients (28.2%). In multivariate analysis, stage and presence of baseline comorbidities, pain, fatigue or malnutrition were associated with HRQOL evolution. CONCLUSION: Baseline HRQOL in older patients with cancer and an abnormal G8 depends on tumor and age related parameters. During follow-up, HRQOL improved in one third of patients, indicating that they may benefit from cancer treatment while one quarter demonstrated a HRQOL decline for which prognostic factors were identified.

Rapid and fatal acute heart failure induced by pazopanib.

Tyrosine kinase inhibitors, represented by sunitinib, sorafenib, axitinib and pazopanib, are emerging molecules harbouring antitumoural efficacy in multiple neoplasia. We report the case of a 51-year-old woman with right thoracic sarcoma who developed fatal heart failure on pazopanib. The patient had no cardiovascular risk factor, except previous exposure to anthracycline, and her cardiac function was normally controlled before initiating the pazopanib. Despite a rapid tumour response, fatigue rapidly appeared, requiring treatment interruption 2 weeks after pazopanib introduction. After clinical improvement, the pazopanib was reintroduced at reduced dose; however, a few days later, our patient was admitted for worsening dyspnoea and fatigue. Pulmonary embolism was excluded as was pleuropericardial effusion. Brain natriuretic peptide was the only laboratory abnormality, and echocardiography revealed acute and severe heart failure. The patient died despite pazopanib arrest and inotropic support.

In vitro sonothrombolysis of human blood clots with BR38 microbubbles.

Microbubble-mediated sonothrombolysis is a promising approach for ischemic stroke treatment. The aim of this in vitro study was to evaluate a new microbubble (MB) formulation (BR38) for sonothrombolysis and to investigate the involved mechanisms. Human whole-blood clots were exposed to different combinations of recombinant tissue plasminogen activator (rtPA), ultrasound (US) and MB. Ultrasound at 1.6 MHz was used at 150, 300, 600 and 1000 kPa (peak-negative pressure). Thrombolysis efficacy was assessed by measuring clot diameter changes during 60-min US exposure. The rate of clot diameter loss (RDL) in µm/min was determined and clot lysis profiles were analyzed. The most efficient clot lysis (5.9 µm/min) was obtained at acoustic pressures of 600 and 1000 kPa in combination with MB and a low concentration of rtPA (0.3 µg/mL). This is comparable with the rate obtained with rtPA at 3 µg/mL alone (6.6 µm/min, p > 0.05). Clot lysis profiles were shown to be related to US beam profiles and microbubble cavitation.

The counterbalanced effect of size and surface properties of chitosan-coated poly(isobutylcyanoacrylate) nanoparticles on mucoadhesion due to pluronic F68 addition.

PURPOSE: To evaluate of the effect of size and surface characteristics of poly(isobutylcyanoacrylate) nanoparticles coated with pluronic F68 and thiolated chitosan on mucoadhesion. METHODS: Nanoparticles were obtained by radical emulsion polymerization in presence of different amounts of F68 (0-4%w/v). Mucoadhesion was ex vivo evaluated by applying nanoparticle suspension on rat intestinal mucosa and quantifying the amount of attached nanoparticles after incubation. RESULTS: F68 unimers added in the polymerization medium allowed decreasing nanoparticle size from 251 to 83 nm, but resulted in nanoparticle surface modification. The amount of thiolated chitosan onto nanoparticle surface was decreased resulting in lower thiol groups and zeta potential. Consequently, the decrease of nanoparticle hydrodynamic diameter resulted in eight-fold-increase of the number of nanoparticles attached to the mucosa but a significant decrease of the weight of attached nanoparticles was observed. This unexpected result was due to a decrease of the amount of chitosan and thiolated chitosan available to interact with mucus upon addition of F68 in the polymerization medium. CONCLUSIONS: Addition of F68 should not be recommended to improve the amount of mucoadherent nanoparticles. Further studies could allow understanding if the low amount of small size nanoparticles could be able to improve oral bioavailability.

Role of the human ST6GalNAc-I and ST6GalNAc-II in the synthesis of the cancer-associated sialyl-Tn antigen.

The Sialyl-Tn antigen (Neu5Acalpha2-6GalNAc-O-Ser/Thr) is highly expressed in several human carcinomas and is associated with carcinoma aggressiveness and poor prognosis. We characterized two human sialyltransferases, CMP-Neu5Ac:GalNAc-R alpha2,6-sialyltransferase (ST6GalNAc)-I and ST6GalNAc-II, that are candidate enzymes for Sialyl-Tn synthases. We expressed soluble recombinant hST6GalNAc-I and hST6GalNAc-II and characterized the substrate specificity of both enzymes toward a panel of glycopeptides, glycoproteins, and other synthetic glycoconjugates. The recombinant ST6GalNAc-I and ST6GalNAc-II showed similar substrate specificity toward glycoproteins and GalNAcalpha-O-Ser/Thr glycopeptides, such as glycopeptides derived from the MUC2 mucin and the HIVgp120. We also observed that the amino acid sequence of the acceptor glycopeptide contributes to the in vitro substrate specificity of both enzymes. We additionally established a gastric cell line, MKN45, stably transfected with the full length of either ST6GalNAc-I or ST6GalNAc-II and evaluated the carbohydrate antigens expression profile induced by each enzyme. MKN45 transfected with ST6GalNAc-I showed high expression of Sialyl-Tn, whereas MKN45 transfected with ST6GalNAc-II showed the biosynthesis of the Sialyl-6T structure [Galbeta1-3 (Neu5Acalpha2-6)GalNAc-O-Ser/Thr]. In conclusion, although both enzymes show similar in vitro activities when Tn antigen alone is available, whenever both Tn and T antigens are present, ST6GalNAc-I acts preferentially on Tn antigen, whereas the ST6GalNAc-II acts preferentially on T antigen. Our results show that ST6GalNAc-I is the major Sialyl-Tn synthase and strongly support the hypothesis that the expression of the Sialyl-Tn antigen in cancer cells is due to ST6GalNAc-I activity.

Contribution of flow cytometry to the diagnosis of malignant and non malignant conditions in lymph node biopsies.

In order to assess the contribution of FC to the diagnosis of lymph node disorders we retrospectively compared the pathological and the FC diagnosis made in 118 consecutive lymph node biopsies. Pathological diagnosis included non malignant conditions (n = 43), B-cell Non Hodgkin lymphoma (NHL) (n = 30), T-cell NHL (1 case), carcinoma (n = 18), Hodgkin lymphoma (HL) (n = 15), melanoma (n = 2), chronic myelocytic leukemia (n = 12), miscellaneous non-lymphoid tissues (n = 6) and undetermined conditions (n = 2). Among the 116 assessable samples, FC was in agreement with histology in 102 cases (87.9%; 95%CI = 81-93) which included 38 benign conditions (90%; 95% CI = 77-97%), 29 NHL (96.7%; 95% CI = 83-100), 18 carcinomas (100%; 95% CI = 81-100), and 12 HL (80.0%; 95% CI = 52-96). Discrepancies (14 cases) included 3 HL undiagnosed by FC and 2 granulomatous adenitis with an erroneous FC diagnosis of HL. Finally, a malignant condition was suspected only by FC in 5 cases (1 carcinoma, 2 B-cell and 2 T-cell NHL) and subsequently demonstrated by additional diagnostic procedures. In conclusion, this study confirms that FC performed on fresh lymph node samples is a powerful diagnostic tool in patients with malignant lymphoma. A few cases left undiagnosed by classical pathological analysis can be recognized by FC. Carcinoma is readily identified by FC analysis, while some benign conditions and Hodgkin lymphoma can be misdiagnosed with the use of FC, although the potential of FC to properly recognize HL is improving compared to previously reported studies. FC is a useful adjunct to pathological analysis of lymph node specimens.

Comparative analysis of the site-specific N-glycosylation of human lactoferrin produced in maize and tobacco plants.

We have compared the site-by-site N-glycosylation status of human lactoferrin (Lf) produced in maize, a monocotyledon, and in tobacco, used as a model dicotyledon. Maize and tobacco plants were stably transformed and recombinant Lf was purified from both seeds and leaves. N-glycopeptides were generated by trypsin digestion of recombinant Lf and purified by reverse-phase HPLC. The N-glycosylation pattern of each site was determined by mass spectrometry. Our results indicated that the N-glycosylation patterns of recombinant Lf produced in maize and tobacco share common structural features. In particular, both N-glycosylation sites of each recombinant Lf are mainly substituted by typical plant paucimannose-type N-glycans, with beta1,2-xylose and alpha1,3-linked fucose at the proximal N-acetylglucosamine. However, tobacco Lf shows a significant amount of processed N-glycans with one or two beta1,2GlcNAc linked to the trimannose core, which are weakly expressed in maize Lf. Finally, no Lewisa epitope was observed on tobacco Lf.

Identification and functional expression of a second human beta-galactoside alpha2,6-sialyltransferase, ST6Gal II.

BLAST analysis of the human and mouse genome sequence databases using the sequence of the human CMP-sialic acid:beta-galactoside alpha-2,6-sialyltransferase cDNA (hST6Gal I, EC2.4.99.1) as a probe allowed us to identify a putative sialyltransferase gene on chromosome 2. The sequence of the corresponding cDNA was also found as an expressed sequence tag of human brain. This gene contained a 1590 bp open reading frame divided in five exons and the deduced amino-acid sequence didn't correspond to any sialyltransferase already known in other species. Multiple sequence alignment and subsequent phylogenic analysis showed that this new enzyme belonged to the ST6Gal subfamily and shared 48% identity with hST6Gal-I. Consequently, we named this new sialyltransferase ST6Gal II. A construction in pFlag vector transfected in COS-7 cells gave raise to a soluble active form of ST6Gal II. Enzymatic assays indicate that the best acceptor substrate of ST6Gal II was the free disaccharide Galbeta1-4GlcNAc structure whereas ST6Gal I preferred Galbeta1-4GlcNAc-R disaccharide sequence linked to a protein. The alpha2,6-linkage was confirmed by the increase of Sambucus nigra agglutinin-lectin binding to the cell surface of CHO transfected with the cDNA encoding ST6Gal II and by specific sialidases treatment. In addition, the ST6Gal II gene showed a very tissue specific pattern of expression because it was found essentially in brain whereas ST6Gal I gene is ubiquitously expressed.