Optimising Alzheimer's Disease Diagnosis and Treatment: Assessing Cost-Utility of Integrating Blood Biomarkers in Clinical Practice for Disease-Modifying Treatment.

BACKGROUND: Recent developments in blood biomarkers (BBM) have shown promising results in diagnosing amyloid pathology in Alzheimer's Disease (AD). However, information on how these BBMs can best be used in clinical settings to optimise clinical decision-making and long-term health outcomes for individuals with AD is still lacking. OBJECTIVES: We aim to assess the potential value of BBM in AD diagnosis within the context of disease-modifying treatment (DMT). DESIGN: We developed a decision analytic model to evaluate the long-term health outcomes using BBM in AD diagnosis. We compared standard of care (SOC) diagnosis workflow to the integration of BBM as a (1) referral decision tool in primary health center (PHC) and (2) triaging tool for invasive CSF examination in specialist memory clinic (MC). We combined a decision tree and a Markov model to simulate the patient's diagnostic journey, treatment decisions following diagnosis and long-term health outcomes. Input parameters for the model were identified from published literature and registry data analysis. We conducted a cost-utility analysis from the societal perspective using a one-year cycle length and a 30-year (lifetime) horizon. MEASUREMENTS: We reported the simulated outcomes in the percentage of correct diagnosis, costs (in 2022 Euros), quality-adjusted life year (QALY), and incremental cost-effectiveness ratios (ICER) associated with each diagnosis strategy. RESULTS: Compared to SOC, integrating BBM in PHC increased patient referrals by 8% and true positive AD diagnoses by 10.4%. The lifetime costs for individuals diagnosed with AD were € 249,685 and €250,287, and QALYs were 9.5 and 9.52 in SOC and PHC pathways, respectively. The cost increments were €603, and QALYs gained were 0.01, resulting in an ICER of €48,296. Using BBM in MC reduced the exposure to invasive CSF procedures and costs but also reduced true positive AD diagnoses and QALYs. CONCLUSIONS: Using BBM at PHC to make referral decisions might increase initial diagnostic costs but can prevent high costs associated with disease progression, providing a cost-effective DMT is available, whereas using BBM in MC could reduce the initial evaluation cost but incur high costs associated with disease progression.

A comparative study of microwave oven-assisted tissue processing and conventional method of tissue processing on turnaround laboratory time and morphological quality of tissue sections.

INTRODUCTION: The purpose of tissue processing is to fix the tissue in a solid medium toenable thin sections. Conventional method of tissue processing is the standardized method of tissue processing which has been used for more than 10 decades. However, the conventional method is time-consuming, and the overall turnaround time for the histopathology report is at least two days. The objective of this study is to identify the protocol for tissue processing procedure using domestic microwave oven. To determine the tissue processing time when using domestic microwave oven. To compare the morphological quality of tissue slides made by domestic microwave oven and conventional method using automated tissue processor. MATRIALS AND METHODS: The conventional protocol and three microwave protocols of tissue processing were used in this study. A pilot study was done prior to the real run to determine the baseline timing for microwave protocol. The baseline timing was fixed at 2 minutes,30 minutes,5 minutes and 25 minutes. The processing time of the microwave protocol was adjusted from 62 minutes to 70 minutes to 77 minutes by increasing the dehydration and wax impregnation time while the time for tissue fixation and clearing remain the same throughout all the microwave protocols. RESULTS: The group 2 microwave protocol produced the sections that is closely comparable to group 1 conventional protocol. The morphological quality of histopathology slides is best observed when the processing time of microwave protocol is 62 minutes. CONCLUSION: The most appropriate microwave protocol for tissue processing is group 2 as the morphological quality of histopathology slides are more superior than that of group 1 with an overall percentage of 80% of satisfactory slides in group 2 and 76.68% in group 1.

Natural fixatives alternative to formalin in histopathology: A systematic review.

INTRODUCTION: Since constant long-term exposure to formaldehyde endangers the health of laboratory personnel, sugar-based natural products have become interesting alternative fixatives to formaldehyde because of their preservative and antibacterial properties. However, there are controversial findings on the fixative effects of natural fixatives. This study systematically reviews the evidence comparing natural fixatives' types, dilutions, fixative properties and staining quality in normal tissues and histopathological specimens. MATERIALS AND METHODS: A comprehensive search was performed for studies comparing the natural fixatives- and formaldehyde-fixed tissues using databases from inception to January 2022: PubMed, Ovid Medline and Google Scholar. Two independent reviewers did data extraction. The data were pooled for the type of natural fixatives, their concentrations and fixative qualities compared to formaldehyde. RESULTS: Fifteen studies were included in this systematic review. Nine studies used one natural fixative with different dilutions, while six used several natural fixatives to compare their fixative properties with formaldehyde. The most used natural fixative was honey (n = 12) followed by jaggery (n = 8), sugar (n = 3) and others (n = 1). Honey showed the most promising results in fixation and staining, which are compatible with formalin. Jaggery and sugar also showed the possibility of replacing formaldehyde in tissue fixation and staining in smaller tissue samples. CONCLUSION: Natural fixatives showed promising results in tissue fixation. However, optimising the concentrations and conditions of natural fixatives is difficult because of the different chemical constituents and production steps. More comprehensive studies are necessary for application.

A Drosophila platform identifies a novel, personalized therapy for a patient with adenoid cystic carcinoma.

Adenoid cystic carcinoma (ACC) is a rare cancer type that originates in the salivary glands. Tumors commonly invade along nerve tracks in the head and neck, making surgery challenging. Follow-up treatments for recurrence or metastasis including chemotherapy and targeted therapies have shown limited efficacy, emphasizing the need for new therapies. Here, we report a Drosophila-based therapeutic approach for a patient with advanced ACC disease. A patient-specific Drosophila transgenic line was developed to model the five major variants associated with the patient's disease. Robotics-based screening identified a three-drug cocktail-vorinostat, pindolol, tofacitinib-that rescued transgene-mediated lethality in the Drosophila patient-specific line. Patient treatment led to a sustained stabilization and a partial metabolic response of 12 months. Subsequent resistance was associated with new genomic amplifications and deletions. Given the lack of options for patients with ACC, our data suggest that this approach may prove useful for identifying novel therapeutic candidates.

USP8 and TP53 Drivers are Associated with CNV in a Corticotroph Adenoma Cohort Enriched for Aggressive Tumors.

CONTEXT: Pituitary corticotroph adenomas are rare tumors that can be associated with excess adrenocorticotropin (ACTH) and adrenal cortisol production, resulting in the clinically debilitating endocrine condition Cushing disease. A subset of corticotroph tumors behave aggressively, and genomic drivers behind the development of these tumors are largely unknown. OBJECTIVE: To investigate genomic drivers of corticotroph tumors at risk for aggressive behavior. DESIGN: Whole-exome sequencing of patient-matched corticotroph tumor and normal deoxyribonucleic acid (DNA) from a patient cohort enriched for tumors at risk for aggressive behavior. SETTING: Tertiary care center. PATIENTS: Twenty-seven corticotroph tumors from 22 patients were analyzed. Twelve tumors were macroadenomas, of which 6 were silent ACTH tumors, 2 were Crooke's cell tumors, and 1 was a corticotroph carcinoma. INTERVENTION: Whole-exome sequencing. MAIN OUTCOME MEASURE: Somatic mutation genomic biomarkers. RESULTS: We found recurrent somatic mutations in USP8 and TP53 genes, both with higher allelic fractions than other somatic mutations. These mutations were mutually exclusive, with TP53 mutations occurring only in USP8 wildtype (WT) tumors, indicating they may be independent driver genes. USP8-WT tumors were characterized by extensive somatic copy number variation compared with USP8-mutated tumors. Independent of molecular driver status, we found an association between invasiveness, macroadenomas, and aneuploidy. CONCLUSIONS: Our data suggest that corticotroph tumors may be categorized into a USP8-mutated, genome-stable subtype versus a USP8-WT, genome-disrupted subtype, the latter of which has a TP53-mutated subtype with high level of chromosome instability. These findings could help identify high risk corticotroph tumors, namely those with widespread CNV, that may need closer monitoring and more aggressive treatment.

A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer.

Colorectal cancer remains a leading source of cancer mortality worldwide. Initial response is often followed by emergent resistance that is poorly responsive to targeted therapies, reflecting currently undruggable cancer drivers such as KRAS and overall genomic complexity. Here, we report a novel approach to developing a personalized therapy for a patient with treatment-resistant metastatic KRAS-mutant colorectal cancer. An extensive genomic analysis of the tumor's genomic landscape identified nine key drivers. A transgenic model that altered orthologs of these nine genes in the Drosophila hindgut was developed; a robotics-based screen using this platform identified trametinib plus zoledronate as a candidate treatment combination. Treating the patient led to a significant response: Target and nontarget lesions displayed a strong partial response and remained stable for 11 months. By addressing a disease's genomic complexity, this personalized approach may provide an alternative treatment option for recalcitrant disease such as KRAS-mutant colorectal cancer.

The Influence of Histologic Subtype in Predicting Survival of Lung Cancer Patients With Spinal Metastases.

STUDY DESIGN: Retrospective analysis. SUMMARY OF BACKGROUND DATA: Recent advancements in systemic treatment of lung cancer have significantly improved the survival of patients with certain histolopathologic and molecular subtypes. Existing prognostic scores do not account for this and patients with lung cancer spinal metastases are grouped together as poor prognostic candidates, and consequently, some may be inappropriately denied palliative spine surgery. OBJECTIVE: The objective of the study was to study whether the expected survival in patients with lung cancer spinal metastases is affected by histolopathologic and molecular subtypes in the context of modern systemic therapy. MATERIALS AND METHODS: We retrospectively reviewed all patients with histologically confirmed lung cancer treated for spinal metastases at our institution between 2001 and 2012. Patients' demographics, histopathologic details, treatment modalities, and survival data were collected. The primary outcome was survival from time of spinal metastases diagnosis. The Cox regression analysis was used to evaluate the influence of tumor histology, molecular profile and treatment modality on survival. The Kaplan-Meier survival analysis was conducted to compare lung cancer subtypes, as well as various treatment regimens. RESULTS: Out of 180 patients, 51 underwent surgery for spinal metastases. Female sex (P=0.019), absence of palsy (P=0.023), good Karnofsky performance scores (P<0.001), and non-small cell lung cancer (NSCLC) (P=0.002) were favorable prognostic factors. Patients who received systemic therapy, including tyrosine kinase inhibitors, platinum doublet chemotherapy, or both showed increased survival (P<0.01). The median survival time was 2.40 months [95% confidence interval (CI), 2.13-2.68] in the small cell lung cancer cohort, with no patients surviving past a year; 5.10 months (95% CI, 3.78-6.41) in the NSCLC cohort, with 25.9% 1-year survival; and 13.3 months (95% CI, 2.26-24.40) in adenocarcinoma patients who received both tyrosine kinase inhibitors and platinum doublet therapy, with 50.0% 1-year survival. CONCLUSIONS: NSCLC, systemic therapy, female sex, absence of palsy and good Karnofsky performance scores are all independent favorable prognostic factors for patients with lung cancer spinal metastases. These should be routinely considered during prognostication.

Identification of a novel RASD1 somatic mutation in a USP8-mutated corticotroph adenoma.

Cushing's disease (CD) is caused by pituitary corticotroph adenomas that secrete excess adrenocorticotropic hormone (ACTH). In these tumors, somatic mutations in the gene USP8 have been identified as recurrent and pathogenic and are the sole known molecular driver for CD. Although other somatic mutations were reported in these studies, their contribution to the pathogenesis of CD remains unexplored. No molecular drivers have been established for a large proportion of CD cases and tumor heterogeneity has not yet been investigated using genomics methods. Also, even in USP8-mutant tumors, a possibility may exist of additional contributing mutations, following a paradigm from other neoplasm types where multiple somatic alterations contribute to neoplastic transformation. The current study utilizes whole-exome discovery sequencing on the Illumina platform, followed by targeted amplicon-validation sequencing on the Pacific Biosciences platform, to interrogate the somatic mutation landscape in a corticotroph adenoma resected from a CD patient. In this USP8-mutated tumor, we identified an interesting somatic mutation in the gene RASD1, which is a component of the corticotropin-releasing hormone receptor signaling system. This finding may provide insight into a novel mechanism involving loss of feedback control to the corticotropin-releasing hormone receptor and subsequent deregulation of ACTH production in corticotroph tumors.

Genomic profiling reveals mutational landscape in parathyroid carcinomas.

Parathyroid carcinoma (PC) is an extremely rare malignancy lacking effective therapeutic intervention. We generated and analyzed whole-exome sequencing data from 17 patients to identify somatic and germline genetic alterations. A panel of selected genes was sequenced in a 7-tumor expansion cohort. We show that 47% (8 of 17) of the tumors harbor somatic mutations in the CDC73 tumor suppressor, with germline inactivating variants in 4 of the 8 patients. The PI3K/AKT/mTOR pathway was altered in 21% of the 24 cases, revealing a major oncogenic pathway in PC. We observed CCND1 amplification in 29% of the 17 patients, and a previously unreported recurrent mutation in putative kinase ADCK1. We identified the first sporadic PCs with somatic mutations in the Wnt canonical pathway, complementing previously described epigenetic mechanisms mediating Wnt activation. This is the largest genomic sequencing study of PC, and represents major progress toward a full molecular characterization of this rare malignancy to inform improved and individualized treatments.

Metastatic Spine Tumor Surgery: A Comparative Study of Minimally Invasive Approach Using Percutaneous Pedicle Screws Fixation Versus Open Approach.

STUDY DESIGN: Prospective cohort study. SUMMARY OF BACKGROUND DATA: Minimally invasive spinal surgery (MISS) has been gaining recognition in patients with metastatic spine disease (MSD). The advantages are reduction in blood loss, hospital stay, and postoperative morbidity. Most of the studies were case series with very few comparing the outcomes of MISS to open approaches. OBJECTIVE: To evaluate and compare the clinical and perioperative outcomes of MISS versus open approach in patients with symptomatic MSD, who underwent posterior spinal stabilization and/or decompression. PATIENTS AND METHODS: Our study included 45 MSD patients; 27 managed by MISS and 18 by open approach. All patients had MSD presenting with symptoms of neurological deficit, spinal instability, or both. Preoperative, intraoperative, and postoperative data were collected for comparison of the 2 approaches. All patients were followed up until the end of study period (maximum up to 4 years from time of surgery) or till their demise. The clinical outcome measures were pain control, neurological and functional status, whereas perioperative outcomes were blood loss, operative time, length of hospital stay, and time taken to initiate radiotherapy/chemotherapy after index surgery. RESULTS: Majority of patients in both groups showed improvement in pain, neurological status, independent ambulation, and ECOG score in the postoperative period with no significant differences between the 2 groups. There was a significant reduction in intraoperative blood loss (621 mL less, P<0.001) in the MISS group. The average time to initiate radiotherapy after surgery was 13 days (range, 12-16 d) in MISS and 24 days (range, 16-40 d) in the open group. This difference was statistically significant (P<0.001). Operative time and duration of hospital stay were also favorable in the MISS group, although the differences were not significant. CONCLUSIONS: MISS is comparable with open approach demonstrating similar improvements in clinical outcomes, that is pain control, neurological and functional status. MISS approaches have also shown promising results due to lesser intraoperative blood loss and allowing earlier radiotherapy/chemotherapy.

Development and clinical application of an integrative genomic approach to personalized cancer therapy.

BACKGROUND: Personalized therapy provides the best outcome of cancer care and its implementation in the clinic has been greatly facilitated by recent convergence of enormous progress in basic cancer research, rapid advancement of new tumor profiling technologies, and an expanding compendium of targeted cancer therapeutics. METHODS: We developed a personalized cancer therapy (PCT) program in a clinical setting, using an integrative genomics approach to fully characterize the complexity of each tumor. We carried out whole exome sequencing (WES) and single-nucleotide polymorphism (SNP) microarray genotyping on DNA from tumor and patient-matched normal specimens, as well as RNA sequencing (RNA-Seq) on available frozen specimens, to identify somatic (tumor-specific) mutations, copy number alterations (CNAs), gene expression changes, gene fusions, and also germline variants. To provide high sensitivity in known cancer mutation hotspots, Ion AmpliSeq Cancer Hotspot Panel v2 (CHPv2) was also employed. We integrated the resulting data with cancer knowledge bases and developed a specific workflow for each cancer type to improve interpretation of genomic data. RESULTS: We returned genomics findings to 46 patients and their physicians describing somatic alterations and predicting drug response, toxicity, and prognosis. Mean 17.3 cancer-relevant somatic mutations per patient were identified, 13.3-fold, 6.9-fold, and 4.7-fold more than could have been detected using CHPv2, Oncomine Cancer Panel (OCP), and FoundationOne, respectively. Our approach delineated the underlying genetic drivers at the pathway level and provided meaningful predictions of therapeutic efficacy and toxicity. Actionable alterations were found in 91 % of patients (mean 4.9 per patient, including somatic mutations, copy number alterations, gene expression alterations, and germline variants), a 7.5-fold, 2.0-fold, and 1.9-fold increase over what could have been uncovered by CHPv2, OCP, and FoundationOne, respectively. The findings altered the course of treatment in four cases. CONCLUSIONS: These results show that a comprehensive, integrative genomic approach as outlined above significantly enhanced genomics-based PCT strategies.

Evaluation of scoring systems and prognostic factors in patients with spinal metastases from nasopharyngeal carcinoma.

BACKGROUND CONTEXT: The decision for operative treatment of patients with spinal metastases is dependent on the patient's predicted survival. Tokuhashi, Tomita, Bauer, and Oswestry scores have been devised for survival prediction; however, none of these systems have been evaluated in nasopharyngeal carcinoma (NPC). PURPOSE: To investigate the accuracy of these scoring systems in predicting survival and to identify prognostic factors for survival of the patients with spinal metastases from NPC. STUDY DESIGN: Retrospective analysis of the patients with spinal metastases from NPC who were treated in our institution. PATIENT SAMPLE: The study included 87 patients with spinal metastases from NPC. OUTCOME MEASURES: The primary outcome measure was the survival time of these patients. The potential prognostic factors that are known to influence survival such as general condition, extraspinal bone metastases, vertebral bone metastases, visceral metastases, and neurologic assessment based on Frankel score were also studied. METHODS: The predicted survival according to the four scoring systems were calculated and labeled as "A" scores. These patients were then rescored by assigning NPC as a good prognostic tumor and labeled as "B" scores. The predicted survival of scores A and B were compared with actual survival. Potential prognostic factors of survival were investigated using univariate and multivariate Cox regression analyses. For all scoring systems, Kaplan-Meier survival estimates and log-rank tests were done; the predictive values were calculated using postestimation after Cox regression analyses. RESULTS: The median overall survival for the whole cohort was 13 (range 1-120) months. In multivariate analysis, general condition (p<.01), visceral metastases (p<.01), and vertebral metastases (p<.01) showed significant association with survival. The absolute score of all scoring systems was significantly associated with actual survival, which extended to the different prognostic subgroups of each scoring systems. Log-rank test revealed significant differences in survival between the different prognostic subgroups of all scoring systems (p<.01). Predictive value of survival by modified Tokuhashi score was the highest among all four scoring systems. CONCLUSIONS: Patients with spinal metastases from NPC have relatively good survival prognosis. All four scoring systems could be used to prognosticate these patients. The modified Tokuhashi score is the best in doing so.

Use of intraoperative cell-salvage for autologous blood transfusions in metastatic spine tumour surgery: a systematic review.

Metastatic spine tumour surgery (MSTS) and metastatic musculoskeletal tumour surgery (MMTS) are associated with substantial blood loss. Allogeneic blood transfusion is the present method used to replenish this blood. Intraoperative cell salvage (IOCS) is a viable alternative, but is contraindicated in tumour surgery because of the risk of tumour dissemination. Use of IOCS-leucocyte depletion filter (LDF) allows removal of tumour cells from blood salvaged during oncological surgery. However, no reports exist on use of IOCS in MSTS or MMTS. We systematically reviewed studies on IOCS in oncological surgery to investigate whether sufficient evidence exists to support its use in MSTS or MMTS.

Periodic lateralized epileptiform discharges (PLEDs) in cerebral lupus correlated with white-matter lesions in brain MRI and reduced cerebral blood flow in SPECT.

This is a case report on an uncommon correlation between periodic lateralized epileptiform discharges (PLEDs) and white-matter lesions in cerebral lupus, and with a reduced cerebral blood flow (CBF) in single-photon emission computed tomography (SPECT). A 47-year-old woman with a long-term history of systemic lupus erythematosus (SLE) presented with a seizure followed by frontal lobe dysfunction clinically. An electroencephalogram (EEG) showed bilateral independent PLEDs in the frontal region. A magnetic resonance image of the brain showed white-matter changes in the frontal periventricular region. Cerebral angiogram did not reveal any evidence of vasculitis. A cerebral SPECT with tracer injected during the EEG showing PLEDs showed a reduction in CBF in the frontal regions. Clinical recovery was observed with intravenous immunoglobulin. This case shows that PLEDs can be seen with white-matter changes in SLE.

Rickets-like radiological and biochemical features of neonatal mucolipidosis II (I-cell disease): report of two cases.

In this paper, two cases with mucolipidosis type II (I-cell disease) (proven in one presenting newborn and presumed in an elder deceased brother) are presented. These infants showed severe skeletal changes with diffuse periosteal new bone formation in long bones and ribs, marked osteopenia, and resorption of scapula, clavicula, and mandible. There was also irregular demineralization of metaphyses of long tubular bones, as seen in rickets. The activities of serum alkaline phosphatase and parathyroid hormone were markedly elevated. Phosphorus was decreased. Serum 1,25-dihydroxyvitamin D was slightly elevated, but 25-hydroxyvitamin D and calcium were normal. Dysostosis multiplex resembling rickets and very high alkaline phosphatase activity were due to defective osteoblastic activity, but the mechanism of elevated parathyroid hormone was not clear. We conclude that early skeletal manifestation of mucolipidosis type II is not clearly identified and that differentiation from congenital rickets or congenital hyperparathyroidism could be difficult. It is speculated that hyperparathyroidism in these patients could be related to the calcium-sensing receptor malfunction in the parathyroid gland.

Early prognostic significance of umbilical cord troponin I in critically ill newborns. Prospective study with a control group.

AIM: To determine the value of cord blood cardiac troponin I levels (cTnl) as an early prognostic factor in critically ill newborns, and to compare cord cTnl levels with the prognostic value of the score for neonatal acute physiology (SNAP). METHODS: Cord arterial samples were collected routinely for blood gas analysis, and cord venous samples for cTnl and cardiac-specific creatine kinase assay. The study group (n=109) comprised critically ill newborns who required mechanical ventilation. The control group (n = 96) comprised newborns who were either completely healthy (n = 48) or were followed in a level I neonatal care unit due to moderate-severity problems. RESULTS: The critically ill newborns had significantly higher cTnl levels than control babies (median [min-max] 1.4 [0-13] vs. 0 [0-1.8] ng/mL, respectively; P<0.001). In critically ill newborns, non-survivors had significantly higher cTnl levels than survivors (median [min-max] 6.6 [1.3-13.0] vs. 1.3 [0-8.0] ng/mL, respectively; P<0.001). Receiver-operator curve analysis revealed that, compared with SNAP, cTnl was a more sensitive predictor of mortality in critically ill newborns (area under curve=0.96; 95% CI=0.90-1.02). CONCLUSION: Significantly elevated cord cTnl may be a valuable predictor of mortality in critically ill newborns.

The impact of national measles immunization programme on measles admissions to the major children's hospital in Yangon.

To ascertain whether measles vaccination was associated with reduced measles associated mortality and morbidity in the Yangon Children's Hospital (YCH), the hospital records of children admitted to YCH in 1985 and 1989 with the diagnosis of measles or measles associated conditions, were analysed retrospectively. Measles vaccination was associated with a 90.7% reduction of deaths directly attributed to measles or ascribed to diarrhoea, respiratory illness, malnutrition or fits. An 85% reduction in the percentage of medical admissions related to measles and measles associated conditions was also seen. The case-fatality rate from measles declined from 25.3% to 15.6%. We conclude that measles immunization has been associated with a marked reduction in morbidity and mortality.