Symptomatic Disease Progression Research Articles

Q-TWiST analysis of pembrolizumab plus trastuzumab and chemotherapy for patients with metastatic HER2-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma in the KEYNOTE-811 trial.

354 Background: In the phase 3 KEYNOTE-811 trial (NCT03615326), first-line pembrolizumab plus trastuzumab and chemotherapy (pembrolizumab group) statistically significantly improved PFS and OS versus placebo plus trastuzumab and chemotherapy (placebo group), with manageable safety, in patients with metastatic HER2-positive G/GEJ adenocarcinoma, while maintaining HRQoL, specifically in patients with PD-L1 combined positive score (CPS) ≥1 tumors. The objective of this analysis was to assess quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) for patients treated in the KEYNOTE-811 trial. Methods: Q-TWiST is a measure of survival weighted by health states utility values. The analysis categorized survival time into 3 health states: time with grade ≥3 adverse events (toxicity [TOX]) and time without symptoms or toxicities (TWiST)—both before disease progression or death—and relapse (REL), defined as time from disease progression to death. Q-TWiST was calculated as the restricted mean survival time spent in each state, with a weighted health state utility for that state. Average utility weights were derived based on pooled EQ-5D-5L scores using the US mapping algorithm and standardized base case utility weights. Relative gains in Q-TWiST of ≥10% and ≥15% were “clinically important” and “clearly clinically important,” respectively, as reported in the literature. Treatment difference 95% CIs were generated using the nonparametric bootstrapping method. Data are reported for patients with PD-L1 CPS ≥1 tumors. The data cutoff date was March 20, 2024. Results: At the maximum follow-up of 63 months, patients in the pembrolizumab group had a 2.36-month (95% CI, −0.24 to 4.56) longer restricted mean time in TOX (6.98 vs 4.63 months), a 3.40-month (95% CI, −0.44 to 7.45) longer restricted mean time in TWiST (12.03 vs 8.62 months), and a 1.45-month (95% CI, −5.84 to 3.09) shorter restricted mean time in REL (8.87 vs 10.32 months) versus the placebo group. For the restricted mean Q-TWIST at month 63, based on the US mapping algorithm, the difference between the pembrolizumab and placebo groups favored the pembrolizumab group by 3.90 months (95% CI, 1.30 to 6.72), representing a 16.57% relative Q-TWiST gain. Based on the standardized base case utility weights, the difference also favored the pembrolizumab group by 3.86 months (95% CI, 1.47 to 6.67), representing a 16.38% relative Q-TWiST gain. Conclusions: Pembrolizumab plus trastuzumab and chemotherapy produced a clearly clinically important improvement in quality-adjusted survival time based on Q-TWiST analyses compared with placebo plus trastuzumab and chemotherapy in patients with previously untreated metastatic HER2-positive G/GEJ adenocarcinoma with PD-L1 CPS ≥1. Clinical trial information: NCT03615326 .

Q-TWiST analysis of pembrolizumab or placebo plus chemotherapy for patients with advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer in KEYNOTE-859.

376 Background: In the phase 3 KEYNOTE-859 study (NCT03675737; N = 1579), patients (pts) with locally advanced or metastatic HER2-negative G/GEJ cancer treated with first-line pembrolizumab (pembro) plus chemotherapy (chemo) had a significant and clinically meaningful improvement in OS with manageable toxicity vs placebo (pbo) plus chemo while maintaining HRQoL in the intention-to-treat and prespecified PD-L1 combined positive score (CPS) populations. We report data from an analysis of quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST). Methods: Q-TWiST is a measure of survival weighted by health states utility values. The analysis categorized survival time into 3 health states: time with grade ≥3 AEs (toxicity [TOX]) and time without symptoms or toxicities (TWiST)—both before disease progression or death—and relapse (REL), defined as time from disease progression to death. Q-TWiST was calculated as the restricted mean survival time (RMST) spent in each state, with a weighted health state utility for that state. Average utility weights were derived based on pooled EQ-5D-5L scores using the US mapping algorithm and standardized base case utility weights. Relative gains in Q-TWiST of ≥10% and ≥15% were “clinically important” and “clearly clinically important,” respectively, as reported in the literature. Treatment difference 95% CIs were generated using the nonparametric bootstrapping method. Data are reported for all randomly assigned pts and pts with PD-L1 CPS ≥1 and CPS ≥10 tumors. The data cutoff date was August 22, 2023. Results: At the maximum follow-up of 56 mo for pembro plus chemo vs pbo plus chemo, RMST was 5.16 vs 2.86 mo for TOX, 7.77 vs 5.87 mo for TWiST, and 6.85 vs 7.12 mo for REL. Between-treatment differences are shown in the table. The difference in restricted mean Q-TWiST and relative gain favored pembro plus chemo. Conclusions: A clearly clinically important Q-TWiST gain was observed for pembro plus chemo vs pbo plus chemo in all pts with advanced HER2-negative G/GEJ cancer and pts with PD-L1 CPS ≥1 and CPS ≥10 tumors. Clinical trial information: NCT03675737 . All ptsN = 1579 PD-L1 CPS ≥1n = 1235 PD-L1 CPS ≥10n = 553 RMST in TOX, mo (95% CI) 2.30(1.28 to 3.44) 2.65(1.46 to 3.99) 4.28(2.08 to 6.41) RMST in TWiST, mo (95% CI) 1.90(−0.02 to 3.79) 2.28(0.07 to 4.49) 3.72(0.43 to 7.19) RMST in REL, mo (95% CI) −0.28(−2.43 to 2.01) −0.22(−2.88 to 2.39) −0.45(−4.52 to 3.71) Restricted meanQ-TWiST, mo (95% CI) a 3.31(2.10 to 4.59) 3.98(2.60 to 5.43) 6.45(4.26 to 8.74) Relative Q-TWiST gain, % (95% CI) a 20.90(12.49 to 30.56) 25.34(16.04 to 36.26) 38.05(23.21 to 56.59) Restricted meanQ-TWiST, mo (95% CI) b 2.91(1.58 to 4.14) 3.50(2.02 to 4.88) 5.63(3.31 to 7.99) Relative Q-TWiST gain, % (95% CI) b 18.38(9.78 to 27.46) 22.27(12.65 to 32.52) 33.19(18.76 to 49.97) a Based on US mapping algorithm. b Based on standardized base case utility weights.

Provider Perspectives and Access to Palliative Care: AnAmerican Head and Neck Society (AHNS) Survey.

To explore provider perspectives about palliative care (PC) in head and neck cancer (HNC) care. A 25-question electronic survey was disseminated to the membership of the American Head and Neck Society (AHNS) from April 10, 2023, through June 13, 2023. Respondents were most likely to refer to PC at symptomatic disease progression (52%) or terminal diagnosis (29%) rather than at initial diagnosis (17%). Participants less likely to refer to PC were less likely to refer to symptomatic progression (8% vs. 39%, p = 0.0006) or address advance directives (62% vs. 87%, p = 0.0406). Symptom burden questionnaires were used by only 29% of respondents. Discordance was identified between self-reported and actual access to local inpatient and outpatient PC services. Barriers to PC identified include a lack of established optimal timing of PC referral, a perceived lack of local access to PC, and a lack of uniform standardized assessment of symptom burden.

Using Implementation Science to Evaluate the Implementation of Patient-Reported Outcome Measures (PROMs) in a Clinical Heart Failure Care Setting

BackgroundPatients with heart failure (HF) can experience a poor quality-of-life (QOL), recurring hospitalizations, and progressive disease symptoms. Patient-reported outcome measures (PROMs) integrate patients’ voices into clinical care, by assessing patient symptoms, function, and QOL. In 2022, PROMs were incorporated into the electronic health record system (Epic) at a large academic hospital in Toronto, Ontario, Canada. The purpose of this study was to use implementation-science frameworks to systematically evaluate the uptake and integration of PROMs into clinical HF care. MethodsThe Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework guided this mixed-methods, 1-year, quality-improvement project. Data sources included the following: clinician use of PROMs; patient-level data on completed PROMs; and semistructured interviews with clinicians. The PROM was the Kansas City Cardiomyopathy Questionnaire-12, which captures 4 domains related to HF—symptom frequency, physical limitations, social limitations, and QOL (KCCQ-12 is used as an example case of PROMs in general). Quantitative data were analyzed using descriptive statistics; qualitative data were analyzed using behaviour-change frameworks and latent content analysis. ResultsOver the course of 1 year, more patients were assigned to PROMs, a higher proportion of patients completed PROMs, and approximately 80% of patients had high scores on the questionnaire. Clinicians experience barriers—related to attention and decision processes, the environmental context, and their professional role—to integrating PROMs into practice. Suggested changes to improve PROM uptake include adding language licenses for PROM translations, reducing cognitive load for clinicians who are assigning and interpreting PROMs in the Epic system, and championing modelling of use of PROMs in practice. ConclusionsThis study demonstrates the benefit of using implementation science frameworks, to evaluate the implementation of PROMs in practice and provide actionable recommendations to health systems.

Effect of Initial Inoculum on the Temporal and Spatial Dynamics of Wheat Blast Under Field Conditions in Bolivia.

Epidemiological studies to better understand wheat blast (WB) spatial and temporal patterns were conducted in three field environments in Bolivia between 2019 and 2020. The temporal dynamics of wheat leaf blast (WLB) and spike blast (WSB) were best described by the logistic model compared with the Gompertz and exponential models. The nonlinear logistic infection rates were higher under defined inoculation in experiments two and three than under undefined inoculation in experiment one, and they were also higher for WSB than for WLB. The onset of WLB began with a spatial clustering pattern according to autocorrelation analysis and Moran's index values, with higher severity and earlier onset for defined than for undefined inoculation until the last sampling time. The WSB onset did not start with a spatial clustering pattern; instead, it was detected later until the last sampling date across experiments, with higher severity and earlier onset for defined than for undefined inoculation. Maximum severity (Kmax) was 1.0 for WSB and less than 1.0 for WLB. Aggregation of WLB and WSB was higher for defined than for undefined inoculation. The directionality of hotspot development was similar for both WLB and WSB, mainly occurring concentrically for defined inoculation. Our results show no evidence of synchronized development but suggest a temporal and spatial progression of disease symptoms on wheat leaves and spikes. Thus, we recommend that monitoring and management of WB should be considered during early growth stages of wheat planted in areas of high risk.

A RARE CASE OF COEXISTING BLADDER SMALL CELL NEUROENDOCRINE CARCINOMA AND PROSTATE ADENOCARCINOMA: CASE REPORT AND LITERATURE REVIEW

Objective: We present a case of synchronous malignancies of rare bladder small cell neuroendocrine carcinoma (SCNC) and prostate adenocarcinoma and provide literature review of bladder SCNC. Case(s) presentation: A 72-year-old male smoker presented with 3 months history of gross hematuria. Ultrasonography showed a large hypoechoic mass in the right bladder. TURBT was performed and histopathology of the TURBT specimen showed a high-grade papillary urothelial carcinoma. Abdominal contrast-enhanced computed tomography (CECT) demonstrated an isodense heterogenous undefined mass, with irregular border at right anterolateral side of bladder wall. Radical cystoprostatectomy, bilateral radical lymph node dissection and bilateral ureterocutaneostomy was performed. Histopathology and immunohistochemical examination after radical cystoprostatectomy revealed bladder small cell neuroendocrine carcinoma coexisting with prostate adenocarcinoma (Gleason score 3+3=6, group 1). The patient eventually succumbed to disease after having symptomatic disease progression and metastatic disease five months after the surgery. Discussion: Bladder SCNC is a rare malignancy with an incidence of 1–9/1,000,000 reported. This tumor has an aggressive clinical course with high incidence of metastasis, and it tends to confer dismal prognosis. No specific clinical symptom exists. Histopathological recognition and immunohistochemistry is required to differentiate this rare entity. Conclusion: Clinicians and pathologists should be alert to the possibility of bladder SCNC despite extremely scarce incidence. Keywords: Bladder cancer, small cell neuroendocrine carcinoma, synchronous malignancy, case report.

392P Quality-adjusted time without symptoms of disease progression or toxicity of treatment (Q-TWiST) analysis to assess benefit-risk of sacituzumab govitecan (SG) in previously treated patients (pts) with metastatic triple-negative breast cancer (mTNBC)

392P Quality-adjusted time without symptoms of disease progression or toxicity of treatment (Q-TWiST) analysis to assess benefit-risk of sacituzumab govitecan (SG) in previously treated patients (pts) with metastatic triple-negative breast cancer (mTNBC)

Assessing the Value of Imaging Data in Machine Learning Models to Predict Patient-Reported Outcome Measures in Knee Osteoarthritis Patients.

Knee osteoarthritis (OA) affects over 650 million patients worldwide. Total knee replacement is aimed at end-stage OA to relieve symptoms of pain, stiffness and reduced mobility. However, the role of imaging modalities in monitoring symptomatic disease progression remains unclear. This study aimed to compare machine learning (ML) models, with and without imaging features, in predicting the two-year Western Ontario and McMaster Universities Arthritis Index (WOMAC) score for knee OA patients. We included 2408 patients from the Osteoarthritis Initiative (OAI) database, with 629 patients from the Multicenter Osteoarthritis Study (MOST) database. The clinical dataset included 18 clinical features, while the imaging dataset contained an additional 10 imaging features. Minimal Clinically Important Difference (MCID) was set to 24, reflecting meaningful physical impairment. Clinical and imaging dataset models produced similar area under curve (AUC) scores, highlighting low differences in performance AUC < 0.025). For both clinical and imaging datasets, Gradient Boosting Machine (GBM) models performed the best in the external validation, with a clinically acceptable AUC of 0.734 (95% CI 0.687-0.781) and 0.747 (95% CI 0.701-0.792), respectively. The five features identified included educational background, family history of osteoarthritis, co-morbidities, use of osteoporosis medications and previous knee procedures. This is the first study to demonstrate that ML models achieve comparable performance with and without imaging features.

Control of Mal secco disease in lemon by drip irrigation with fungicide

Mal secco disease of citrus is caused by the mitosporic ascomycete fungus Plenodomus tracheiphilus (formerly Phoma tracheiphila [Petri]). Mal secco is a highly destructive vascular disease of lemon and other citrus which is presently confined to the Mediterranean basin and has a marked economic impact on the citrus industry. The fungal pathogen infects the host tree by penetrating through wounds in the roots or canopy. Infection spreads quickly into the main branches and trunk and tree mortality usually ensues. The most typical symptoms are veinal chlorosis, leaf wilt, red discoloration of the xylem and dieback of twigs and branches. Current accepted control of the disease is mainly by sanitation of infected wood, and copper application during the winter to prevent germinating spores from infecting the plant. No effective chemical control for this disease has been reported. We present a drip-irrigation protocol to protect trees and control the disease in which we apply 250 g/ha of the triazole fungicide flutriafol five times a year. Progression of disease symptoms in the treated trees was inhibited by up to 81% compared to the untreated control, thereby significantly shortening the sanitation process and making it less costly than in untreated trees. Moreover, disease symptoms became less severe as the duration of treatment increased. We have treated orchards for 3 years, and present an effective commercial protocol for the growers which will help them control Mal secco disease.

Genetic therapies for cardiomyopathy: survey of attitudes of the patient community for the CureHeart project

Cardiomyopathies are a group of inherited heart muscle disorders. Expressivity is variable and while sometimes mild, complications can result in sudden cardiac death (SCD) at any age, heart failure and stroke. In around a third of patients a monogenic cause is identifiable, and development of genetic therapies that aim to correct the underlying genetic defect is underway. Here we describe results of a survey designed to understand preliminary views of the patient community about genetic therapies in the context of disease burden. The internet survey was publicized with a bespoke information video via patient support groups in the UK and USA; 634 people responded of whom 96% had a personal and/or family history of cardiomyopathy. Findings show that concern about cardiomyopathy-related issues with a future dimension, such as disease progression, is significantly greater than concern about current issues. A total of 93.6% thought that genetic therapies should be developed for cardiomyopathy. A majority would consider participation in a genetic therapy trial in six scenarios varying by age and clinical situation significantly more in the scenario of an adult with symptomatic disease and evident progression than an asymptomatic adult with SCD risk, or a child. In all scenarios, a majority said that the chance genetic therapy would stop or slow progression, and risk of serious adverse and unintended effects, were important considerations. Qualitative analysis of free-text responses found that concern was often informed by family experience. Patient consideration of genetic therapy is likely to require individualized assessment of the benefits and risks.

A quality-adjusted time without symptoms and toxicity (Q-TWiST) analysis comparing nivolumab plus ipilimumab (N+I) or nivolumab plus chemotherapy (N+CT) versus CT in patients (pts) with advanced esophageal squamous cell carcinoma (ESCC): CheckMate 648.

251 Background: In CheckMate 648, pts with advanced ESCC treated with first-line N+I or N+CT had significantly longer overall survival (OS) vs CT and maintained quality of life (QoL) with no new safety signals. Here we compare between-treatment differences in quality-adjusted survival using a Q-TWiST analysis in all randomized pts (29-month minimum follow-up). Methods: Survival time was partitioned into 3 health states: toxicity (TOX), time without symptoms of disease progression or toxicity (TWiST), and relapse (REL). TOX was defined as time spent with all-cause grade 3/4 adverse events after randomization, prior to disease progression. TWiST was defined as time prior to REL where pts did not experience TOX. REL was defined as time between disease progression and death, or the last known date alive. Mean duration of time in each state was calculated for each treatment group using descriptive statistics and Kaplan-Meier analysis. Utility values from the 3-level EQ-5D (EQ-5D-3L) questionnaire were used to adjust the time spent within each health state for QoL and to calculate Q-TWiST as the utility-weighted sum of the mean health state durations. Bootstrapping (500 samples) was used to estimate time in each health state and to compare mean Q-TWiST estimates between treatments. A between-group difference in Q-TWiST of 5 weeks was prespecified as being clinically important (defined as 10% of OS; based on a median OS in CT group of 10.7 months). Sensitivity analyses were conducted using different combinations of prespecified utility weights for each health state. Results: 970 pts were randomized 1:1:1 to N+I (n = 325), N+CT (n = 321), or CT (n = 324) and included in the Q-TWiST analysis. Median duration of follow-up for survivors was 155 weeks. Mean time in each health state was significantly longer for pts treated with N+I or N+CT compared to CT (Table). Between-group differences in Q-TWiST score were considered clinically important: 5.7 weeks (95% CI 5.5–6.0) favoring N+I vs CT and 7.6 weeks (95% CI 7.4–7.9) favoring N+CT vs CT. Sensitivity analyses supported these findings. Conclusions: In CheckMate 648, pts with unresectable advanced ESCC treated with N+I or N+CT had significantly longer OS compared with those treated with CT. Quality-adjusted survival using Q-TWiST also significantly favored N+I and N+CT compared to CT alone. Pts treated with N+I and N+CT not only experienced increased survival time, but also better QoL during their survival time. Clinical trial information: NCT03143153 . [Table: see text]

Symptomatic idiopathic pulmonary artery aneurysm: a case report and a mini-review of the literature.

Pulmonary artery aneurysms (PAAs) are rare, more prevalent in younger population with equal sex incidence. Congenital, idiopathic, autoimmune, infectious, inflammatory, and malignant etiologies have been linked to PAAs. Commonly, patients with PAA are asymptomatic, even those with large PAAs. Presenting symptoms, if any, are non-specific. The management should target the underlying conditions and serial imaging follow-up. Signs and symptoms of disease progression should prompt a change in treatment strategy. Though there is no consensus, those who are symptomatic with a PAA diameter > 5 cm generally should undergo surgical repair. More recently, endovascular interventions are available for certain PAAs. We present a 78-year-old female who was referred to the cardiology clinic for cough and dyspnea. Using computed tomography (CTA) of the chest, she was diagnosed with aneurysm of the main pulmonary artery (PA), without involvement of distal pulmonary arteries or thoracic aorta. She underwent repair of the pulmonary artery using a 34-mm tubular graft with a complete resolution of her symptoms.

Carltonine-derived compounds for targeted butyrylcholinesterase inhibition.

The investigation into human butyrylcholinesterase (hBChE) inhibitors as therapeutic agents for Alzheimer's disease (AD) holds significant promise, addressing both symptomatic relief and disease progression. In the pursuit of novel drug candidates with a selective BChE inhibition pattern, we focused on naturally occurring template structures, specifically Amaryllidaceae alkaloids of the carltonine-type. Herein, we explored a series of compounds implementing an innovative chemical scaffold built on the 3- and 4-benzyloxy-benzylamino chemotype. Notably, compounds 28 (hBChE IC50 = 0.171 ± 0.063 μM) and 33 (hBChE IC50 = 0.167 ± 0.018 μM) emerged as top-ranked hBChE inhibitors. In silico simulations elucidated the binding modes of these compounds within hBChE. CNS availability was predicted using the BBB score algorithm, corroborated by in vitro permeability assessments with the most potent derivatives. Compound 33 was also inspected for aqueous solubility, microsomal and plasma stability. Chemoinformatics analysis validated these hBChE inhibitors for oral administration, indicating favorable gastrointestinal absorption in compliance with Lipinski's and Veber's rules. Safety assessments, crucial for the chronic administration typical in AD treatment, were conducted through cytotoxicity testing on human neuroblastoma (SH-SY5Y) and hepatocellular carcinoma (HepG2) cell lines.

Environmental Exposure to Trace Elements and Heavy Metals Preceding the Clinical Onset of Inflammatory Bowel Disease.

The immune dysregulation underlying inflammatory bowel disease (IBD) can start years before the diagnosis, but the role of triggering factors and environmental exposures during this period is still uncertain. This single-center case-control study included asymptomatic subjects with an incidental diagnosis of IBD during the colorectal cancer screening program. Twenty-two minerals and 17 metals were determined at diagnosis in hair samples and compared 1:2 to healthy controls. Six patients with preclinical IBD (3 ulcerative colitis, 67% left-sided; 3 Crohn's disease, 100% ileal, 67% inflammatory behavior) and 13 healthy non-IBD controls were included. No relevant occupational exposures were identified. We found statistically significant higher levels of sodium, potassium, and boron among cases compared to controls; while lower levels of zinc, uranium, copper, and germanium were observed. A range of environmental exposures can be identified during the preclinical phase of IBD, but their relationship with the symptomatic onset and disease progression should be further explored.

Clinical Features of Essential Tremor in the Two Ethnic Groups

Objective: The aim of the study was to study the clinical features of essential tremor (ET) in residents of the Republic of Sakha (Yakutia) in various ethnic groups.Material and methods. The study involved 53 patients with an established diagnosis of essential tremor. All patients underwent a detailed neurological examination with a quantitative assessment of the severity and severity of tremor, as well as the degree of maladjustment and activity in everyday life using unified scales.Results and Discussions. It was revealed that the clinical variant of essential tremor-plus, associated with a more severe course and disability of patients. In the representatives of the Russian ethnic group, with the classic version of essential tremor, a combination of head tremor and hand tremor is observed, as well as a more rapid progression of disease symptoms. Representatives of the Yakut ethnic group in the clinical picture of essential tremor-plus are statistically significantly more likely to have a dystonic head position.Conclusion. Clinical variability of essential tremor with differences in the ethnic aspect in the rate of progression and in the frequency of the combination of action tremor with dystonic head position was demonstrated.

Rationale and design of the prognostic transcriptomic signature in fibrotic hypersensitivity pneumonitis (PREDICT) study.

Hypersensitivity pneumonitis is an immunologically mediated form of lung disease, resulting from inhalational exposure to a large variety of antigens. A subgroup of patients with fibrotic hypersensitivity pneumonitis (FHP) develop symptomatic, functional and radiographic disease progression. Mortality occurs primarily from respiratory failure as a result of progressive and self-sustaining lung injury that often occurs despite immunosuppression and removal of the inciting antigen. The development and validation of a prognostic transcriptomic signature for FHP (PREDICT-HP) is an observational multicentre cohort study designed to explore a transcriptomic signature from peripheral blood mononuclear cells in patients with FHP that is predictive of disease progression. This article describes the design and rationale of the PREDICT-HP study. This study will enrol ∼135 patients with FHP at approximately seven academic medical sites. Participants with a confirmed diagnosis of FHP are followed over 24 months and undergo physical examinations, self-administered questionnaires, chest computed tomography, pulmonary function tests, a 6-min walk test and blood testing for transcriptomic analyses. At each 6-month follow-up visit the study will assess the participants' clinical course and clinical events including hospitalisations and respiratory exacerbations. The PREDICT study has the potential to enhance our ability to predict disease progression and fundamentally advance our understanding of the pathobiology of FHP disease progression.

Predicting disease progression and the need for tumor-directed treatment in tectal plate gliomas.

Tectal plate gliomas are rare, slow-growing tumors of the midbrain that are discovered predominantly in the pediatric population. Because of their indolent nature, treatment mainly consists of observation and management of hydrocephalus. Unfortunately, a subset of tectal gliomas may exhibit tumor enlargement and disease progression. Currently, there are no established guidelines for predicting future progression of tectal gliomas or the need for tumor-directed treatment. In this paper, the authors present a large case series of tectal plate gliomas with the aim of determining early indicators of tumor progression and the need for tumor-directed treatment in a pediatric population, along with providing their experience in treating progressive tumors. A retrospective chart review of 170 patients diagnosed with tectal plate glioma from a single institution, of whom 67 were pediatric patients (≤ 18 years of age), was performed. Univariate analysis was used to determine statistically significant predictors of symptomatic disease progression requiring eventual tumor-directed therapy. The median patient age of the full cohort was 24 years (range 0-73 years). Compared with the pediatric population, the adult population had more instances of incidental lesions (p < 0.001) and lower rates of hydrocephalus (50% vs 84%, p < 0.001). Of the pediatric patients who had ≥ 5 years of follow-up (n = 51), 12 (24%) experienced radiological progression and 13 (25%) required treatment for their tumor. The 1-year, 5-year, and 10-year radiographic progression-free survival (PFS) rates were 98%, 90%, and 86%, respectively. In univariate analysis, lesion involvement of the pons, moderate T1 hypointensity, and moderate contrast enhancement on baseline radiology were significantly associated with worse radiographic PFS. Alternatively, significant predictors of requiring tumor-directed treatment included extraocular eye movement abnormalities at presentation, involvement of the lesion beyond the tectum on baseline radiology, moderate T1 hypointensity, moderate contrast enhancement, and an increase in total lesion size during progression. At the most recent follow-up, 94% of the patients had stable/nonprogressive disease, 2% had progressive disease, and 4% died of tumor progression. Patients who demonstrate radiographic progression may not necessarily experience clinical/symptomatic progression or require tumor-directed treatment. Certain patient presentation characteristics and baseline radiographic features may be predictive of worse radiographic PFS or the need for future tumor-directed treatment in the pediatric population. Typically, the natural history of these lesions lends to excellent long-term survival, even in patients who experience clinical progression, should appropriate treatment be initiated.

Genes, inflammatory response, tolerance, and resistance to virus infections in migratory birds, bats, and rodents.

Normally, the host immunological response to viral infection is coordinated to restore homeostasis and protect the individual from possible tissue damage. The two major approaches are adopted by the host to deal with the pathogen: resistance or tolerance. The nature of the responses often differs between species and between individuals of the same species. Resistance includes innate and adaptive immune responses to control virus replication. Disease tolerance relies on the immune response allowing the coexistence of infections in the host with minimal or no clinical signs, while maintaining sufficient viral replication for transmission. Here, we compared the virome of bats, rodents and migratory birds and the molecular mechanisms underlying symptomatic and asymptomatic disease progression. We also explore the influence of the host physiology and environmental influences on RNA virus expression and how it impacts on the whole brain transcriptome of seemingly healthy semipalmated sandpiper (Calidris pusilla) and spotted sandpiper (Actitis macularius). Three time points throughout the year were selected to understand the importance of longitudinal surveys in the characterization of the virome. We finally revisited evidence that upstream and downstream regulation of the inflammatory response is, respectively, associated with resistance and tolerance to viral infections.

Understanding disease pathogenesis and host response of endemic malaria in previously exposed individuals compared to naïve individuals

Plasmodium falciparum and Plasmodium vivax are two major species of malaria that can establish a focus of infection in millions of individuals per year. Principally, this occurs in the tropical and subtropical regions of the world where malaria is endemic due to the ubiquity of the disease vector, the Anopheles mosquitos. Malaria takes the lives of thousands of infected individuals as the progression of disease symptoms having fatal consequences. This disease mainly affects children and pregnant women which poses a great public health concern. It is also a global economic burden from the millions of international dollars are aliquoted for research yearly. This review looks to discuss the pathogenesis of malaria, various host immune responses, the development of clinical immunity in reinfected individuals, and the effects that the presence of one species may have on the pathogenesis and disease outcome of another malarial species in co-infected individuals. Overall, this manuscript aims to provide an understanding of malarial infection and the differing host immune mechanisms of previously exposed individuals compared to those of naïve individuals in environments where malaria is of high prevalence. These highlights indicate a need for further research in order to better understand host-species and species-species interactions so that proper therapeutics and vaccinations may be developed as to not inhibit the beneficial effects species may have on one another in mixed species interactions as well as to aid in the development of clinical immunity.

Best practices in epidermal growth factor receptor T790M testing for advanced non-small-cell lung cancer in Hong Kong.

The T790M mutation in the epidermal growth factor receptor gene causes most acquired resistance to firstor second-line epidermal growth factor receptor-tyrosine kinase inhibitors in advanced non-small-cell lung cancer. The results of T790M testing can guide subsequent treatment. Despite the availability of guidelines from international organisations, T790M testing practices in Hong Kong must be streamlined and adapted to the Hospital Authority setting. To address this issue, a panel of experts in oncology and pathology met for discussion of key topics regarding T790M testing practices in Hong Kong, including the appropriate timing of testing and re-testing, as well as optimal testing methods. All panel members voted on the results of the discussion to achieve consensus. Items supported by a majority vote were adopted as consensus statements regarding current best practices for T790M testing in Hong Kong. Among the topics discussed, the panel agreed that T790M testing should be initiated upon radiological progression, including symptomatic disease progression or central nervous system-only progression. The experts also preferred initial testing with liquid biopsy, using the widely available digital polymerase chain reaction platform. This document provides the final consensus statements, as well as a testing and treatment workflow, for clinicians in Hong Kong to use as guidance in T790M testing.