bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of bleeding event frequency on health-related quality of life and work productivity outcomes in a European cohort of adults with haemophilia A: insights from the CHESS II study
Authors: Young Lisa , Chen Yong , Alvir José , Burke Tom , Ferri Grazzi Enrico , Winburn Ian
Published: August 2023

Background

Haemophilia A carries a substantial healthcare burden, affecting health-related quality of life (HRQoL). The Cost of Haemophilia in Men: a Socioeconomic Survey II (CHESS II), a retrospective real-world study, characterised the burden of haemophilia and its impact on HRQoL and work productivity. The current analysis explored the impact of bleeding events on HRQoL and work productivity in Europe. This analysis focused on data collected from males aged 18 to 64 years with haemophilia A without inhibitors who were receiving replacement factor products or a monoclonal antibody and were not participating in a clinical trial at the time of study recruitment. Descriptive statistics were analysed using scores from EuroQoL’s EQ-5D-5L index and EQ-VAS analogue scale and the Work Productivity and Activity Index Specific Health Problem (WPAI:SHP) percentage scores stratified by the number of annual bleeding events (ABs) 0, 1, 2, 3–4, or ≥ 5.

Results

Of 918 males with haemophilia A in CHESS II, 318 met inclusion criteria and had data available for HRQoL measures; mean age (SD) was 33.8 (12.1) years and 96% were White. Mean (SD) ABs of 2.7 (2.9) occurred over the preceding 12 months: 20% had 3 or 4 ABs; 17% had ≥ 5 ABs. Mean EQ-5D-5L index scores for patients with 0, 1, 2, 3–4, or ≥ 5 ABs were 0.92, 0.76, 0.76, 0.71, and 0.56, respectively. Mean (SD) EQ-VAS scores were 86.9 (13.6), with 0 ABs versus 69.5 (19.1) for 3 or 4 ABs and 61.2 (17.2) for ≥ 5 ABs. Mean percentage of overall work productivity loss on the WPAI:SHP questionnaire ranged from 9.70 to 0 ABs to 47.65 for ≥ 5 ABs.

Conclusions

In this European sample of adult men with haemophilia A, HRQoL and work productivity scores were lower among those reporting more AB events. Bleeding burden appears to affect HRQoL and productivity; however, this cross-sectional analysis limits the ability to draw firm conclusions on causality.
Intrathecal magnesium delivery for Mg++-insensitive NMDA receptor activity due to GRIN1 mutation
Authors: Lewis Sara A. , Shetty Sheetal , Gamble Sean , Heim Jennifer , Zhao Ningning , Stitt Gideon , Pankratz Matthew , Mangum Tara , Marku Iris , Rosenberg Robert B. , Wilfong Angus A. , Fahey Michael C. , Kim Sukhan , Myers Scott J. , Appavu Brian , Kruer Michael C.
Published: August 2023

Background

Mutations in the NMDA receptor are known to disrupt glutamatergic signaling crucial for early neurodevelopment, often leading to severe global developmental delay/intellectual disability, epileptic encephalopathy, and cerebral palsy phenotypes. Both seizures and movement disorders can be highly treatment-refractory.

Results

We describe a targeted ABA n-of-1 treatment trial with intrathecal MgSO4, rationally designed based on the electrophysiologic properties of this gain of function mutation in the GRIN1 NMDA subunit.

Conclusion

Although the invasive nature of the trial necessitated a short-term, non-randomized, unblinded intervention, quantitative longitudinal neurophysiologic monitoring indicated benefit, providing class II evidence in support of intrathecal MgSO4 for select forms of GRIN disorders.
CD20 × CD3 bispecific antibodies for lymphoma therapy: latest updates from ASCO 2023 annual meeting
Authors: Liu Xinyuan , Zhao Juanjuan , Guo Xiangqian , Song Yongping
Published: August 2023

Multiple bispecific antibodies (bsAbs) have been approved for cancer immunotherapy. Several CD20 × CD3 bsAbs have demonstrated significant anti-B-cell non-Hodgkin lymphoma (NHL) activity by engaging T cells to target CD20+ NHL cells in clinical trials. Mosunetuzumab, epcoritamab and glofitamab have been approved recently for B-cell NHL therapy. In this study, we summarized several latest reports on CD20 × CD3 bsAbs for the therapy of B-cell NHL from the ASCO 2023 annual meeting (ASCO2023).
Progressive encephalomyelitis with rigidity and myoclonus (PERM) associated with anti-glycine receptor antibodies and urothelial carcinoma: a case report
Authors: Ali Amanuel Hassen , Benterud Anna , Holmøy Trygve , Myro Aija Zuleron
Published: August 2023

Background

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare neurological condition with paraneoplastic etiology in about 20% of cases, usually presenting before or shortly after the oncological diagnosis is established. PERM associated with anti-glycine receptor antibodies is not previously reported in a patient with bladder cancer.

Case presentation

A 72-years-old Caucasian male was admitted with acute onset of dysarthria, dysphagia and trismus three years after initial surgical treatment for bladder cancer. The condition was initially diagnosed as tetanus and treated accordingly, but the diagnosis was reconsidered because of progression despite adequate treatment. Diagnostic workup on readmission revealed lung and paraaortal metastases from bladder cancer and anti-glycine receptor (anti-GlyR) antibodies both in the cerebrospinal fluid and in serum, which supplemented with the clinical presentation led to the diagnosis of PERM, presumably related to bladder cancer. The patient showed improvement and stabilization after treatment with intravenous immunoglobulin and chemotherapy against metastatic bladder cancer.

Conclusion

To the best of our knowledge, this is the first reported case of anti-GlyR antibody positive PERM related to urothelial carcinoma. The symptoms mimicked tetanus, and responded to chemotherapy and immunotherapy.
Variational inequality arising from variable annuity with mean reversion environment
Authors: Jeon Junkee , Kim Geonwoo
Published: August 2023

In this paper, we study a variational inequality arising from variable annuity (VA) to find the optimal surrender strategy for a VA investor when the underlying asset follows a mean reverting process. We formulate the problem as a free boundary partial differential equation (PDE) to obtain the optimal strategy. The PDE is solved analytically by the Mellin transform approach. Using the Mellin transform, we derive the integral equations for the value of the VA and the optimal surrender boundary. Since the solutions are obtained as the integral equations, we use the recursive integration method to determine the optimal surrender strategy. Finally, we provide the optimal surrender boundaries and values of VA with respect to some significant parameters to show the impacts of mean reversion.
An evaluation of transfer learning models in EEG-based authentication
Authors: Yap Hui Yen , Choo Yun-Huoy , Mohd Yusoh Zeratul Izzah , Khoh Wee How
Published: August 2023

Electroencephalogram(EEG)-based authentication has received increasing attention from researchers as they believe it could serve as an alternative to more conventional personal authentication methods. Unfortunately, EEG signals are non-stationary and could be easily contaminated by noise and artifacts. Therefore, further processing of data analysis is needed to retrieve useful information. Various machine learning approaches have been proposed and implemented in the EEG-based domain, with deep learning being the most current trend. However, retaining the performance of a deep learning model requires substantial computational effort and a vast amount of data, especially when the models go deeper to generate consistent results. Deep learning models trained with small data sets from scratch may experience an overfitting issue. Transfer learning becomes an alternative solution. It is a technique to recognize and apply the knowledge and skills learned from the previous tasks to a new domain with limited training data. This study attempts to explore the applicability of transferring various pre-trained models’ knowledge to the EEG-based authentication domain. A self-collected database that consists of 30 subjects was utilized in the analysis. The database enrolment is divided into two sessions, with each session producing two sets of EEG recording data. The frequency spectrums of the preprocessed EEG signals are extracted and fed into the pre-trained models as the input data. Three experimental tests are carried out and the best performance is reported with accuracy in the range of 99.1–99.9%. The acquired results demonstrate the efficiency of transfer learning in authenticating an individual in this domain.
Implementation of patient navigation program: Experience in Cipto Mangunkusumo Hospital as one of the first pilot projects in Indonesia.
Authors: Giselvania Angela , Radityamurti Fahmi , Gondhowiardjo Soehartati
Published: August 2023

104

Background: Successful cancer treatment depends on many factors, not merely only medical aspects, but also other things, such as patients’ ability to comply the treatment schedule, patients’ understanding of the treatment steps and process, to avoid delay in administrative process, etc. These non-medical aspects are significantly affects patients ability to complete the treatment, especially in developing country including Indonesia. This study aims to empower a group of patient navigator (PN) in a Radiation Oncology Unit in one of the biggest national top referral hospital in Indonesia, Cipto Mangunkusumo Hospital. Methods: For the preparation of the project, 14 lay patient navigators and 1 physical navigator who were all cancer survivors nor volunteer from the Cancer Information and Support Center (CISC) Group, were trained for basic patient navigation training and basic cancer knowledge, as well as communication skills training. The navigators also trained for emergency response (basic life support, hospital emergency codes and responses, etc). This program is under supervision of the American Cancer Society (ACS). As for the flow of the process, all new cancer patients in the Department will be introduced to PN for screening of their non-medical aspects potential barriers using a self-made questionnaire. Fourteen risk potential problems are listed in the questionnaires, including accommodation, transportation, financial, psycho-social and family/support system problems. Results: The program was launched in September 2022 in the Department of Radiation Oncology Cipto Mangunkusumo Hospital. Patients with all cancer types are included in the program. Until Feb 2023, more than 500 patients have been screened for their potential barriers in going through the treatment. Most of the significant helps given by the PN were allocating a free accommodation for the patients living far from the hospital, free transportation pick up to the hospital, home visits for those who drop outs from treatment and give the supports needed to come back to therapy, and psychosocial-emotional supports. Conclusions: Patient navigation program in our Department was found to be effective in helping our cancer patients completing their treatment.
Factors associated with adverse outcome in pediatric oncology patients with febrile neutropenia: A prospective cohort study from India.
Authors: Dabas Aditya , Sharma Vagisha , Singh Amitabh , Kriplani Kushal , Gaind Rajni , Gera Rani
Published: August 2023

117

Background: Febrile neutropenia is a frequent complication in pediatric cancer patients on chemotherapy. Mortality rates from infections in this population range from 0.1-4%. Several studies from developed countries have reported the duration of fever, duration of neutropenia, comorbidities, absolute monocyte count (AMC), CRP, etc to be important predictors of a high-risk FN episode. Low medium-income countries' (LMIC) outcome data lags behind those from developed countries. Infection-associated mortality in children with febrile neutropenia is one of the major contributors to adverse outcomes. The study aims to find predictors of mortality in children with febrile neutropenia in low-income settings. Methods: A prospective cohort study of children aged 1-12 years who developed Febrile neutropenia with ongoing chemotherapy was carried out between 1st November 2019 to 31st March 2021. A comprehensive history related to demography, symptomatology, underlying disease, treatment and febrile neutropenia was documented. Study participants were followed up till the end point of the study to record outcomes. Results: A total of 131 children(mean age 6.57 years) were enrolled in the study. Of these 77.1% were males. The majority of patients had ALL (64.1 % had B cell and 20.6% had T cell ALL) followed by AML(8.4%) and Non-Hodgkin lymphoma(3.8%). The average length of hospital stay was 10 days. In-hospital mortality was 9.2%. Duration of hospitalization of more than 10 days and that of febrile neutropenia of more than a week were found to be independently associated with mortality. Absolute phagocyte counts of less than a hundred(9.1%), hemodynamic instability(29.2%), and Grade 3-4 undernutrition(8.4%) were also associated with increased mortality. Lower Absolute neutrophil count and higher procalcitonin levels on days 3 and 5 of hospitalization were also associated with patient mortality. Gender, age, baseline cancer diagnosis and infection profile during FN episode did not affect patient outcome. The cycle of chemotherapy and the time since the last dose did not affect patient outcomes. Conclusions: Malnutrition, duration of hospital stay, duration of neutropenia, absolute phagocytic count, hemodynamic instability, procalcitonin, and absolute neutrophil count were independent risk factors of mortality. Overall mortality in our study was 9.1 %. In LMIC, mortality remains high due to poor hygiene, the low education level of the population, and poor socioeconomic status.
Trajectories of depression and anxiety among older cancer survivors: A group-based trajectory analysis of a nationally representative cohort.
Authors: Pu Junlan , Pu Junlan , Shang Shaomei , Zeng Wen
Published: August 2023

130

Background: Depression and anxiety are common for cancer survivors, especially those aged 65 years or older, which are negatively associated with quality of life and survival. A few studies have described the average population level of longitudinal change in depression and anxiety, but they may not capture the inter-individual variability of the longitudinal trajectory, especially in older cancer survivors. The aims of the current study were to (1) describe the trajectory patterns of depression and anxiety over time among older cancer survivors; (2) examine the socio-demographic and health-related predictors of different subgroups of trajectories. Methods: We used data from the National Health and Aging Trends Study (NHATS), a nationally representative cohort study. The Generalized Anxiety Disorder-2 scale and Patient Health Questionnaire-2 were used to assess levels of depression and anxiety. The group-based trajectory model was used to identify the distinct trajectories of depression and anxiety from 2015 to 2021. Design-based multinomial logistic regression was used to examine the socio-demographic and health-related predictors of different trajectories. All analyses accounted for the complex sample design (stratification and primary sampling units) and survey weights. Results: A total of 1,766 older cancer survivors were included, and the average prevalence of depression and anxiety from 2015 to 2021 was 27.14%. Four trajectories of depression and anxiety were identified: robust (48.9%), deteriorating (24.1%), meliorating (11.0%), and sustained-high (16.1%). Older cancer survivors were at a sustained-high depression and anxiety trajectory if they were older, female, reported poorer health, had a worse cognitive function, and had more difficulty in activities of daily living ( P<0.05). Conclusions: Our findings highlight the heterogeneity and complexity of the depression and anxiety process in older cancer survivors. This study helps identify patients at a high risk of depression and anxiety and develop more individualized strategies to ameliorate the mental health of older cancer survivors.
Clinical validation of a ctDNA-based assay for multi-cancer detection: An interim report from a Vietnamese longitudinal prospective cohort study of 2795 participants.
Authors: Nguyen Hanh Thi-Hue , Tran Le Son
Published: August 2023

135

Background: Cancer is a major public health and economic issue and is the leading cause of death worldwide. Up to 80% of cancer patients in Vietnam were diagnosed at stage III or stage IV, leading to a a low 5-year survival rate compared to other countries. Early cancer screening assays capable of identifying early-stage cancer patients among high-risk or asymptomatic individuals are essential to achieve better treatment outcomes and reduced mortality. We previously developed a multimodal LB-based assay named Screening for the Presence Of Tumor by Methylation And Size (SPOT-MAS) to detect the five most common cancer types in Vietnam (liver, breast, colorectal, gastric, and lung cancer). To be successfully applied as a population-wide screening test, the clinical performance of SPOT-MAS needs to be validated in a prospective study. Methods: Herein, we launched a prospective cohort study named K-DETEK (ClinicalTrials.gov identifier: NCT05227261) at 13 major hospitals and one research institute in Vietnam to assess the feasibility and performance of SPOT-MAS in a multi-center clinical trial setting. Our study recruited 10,000 asymptomatic participants participants aged 40 years or older and followed-up for 6 and 12 months. The performance was assessed by computing the number of cases with the detection of a signal (n, %), including a positive predictive value (PPV) and accuracy in detecting tumor tissue-of-origin (TOO). Results: At the time of abstract submission, our analysis of 2795 participants demonstrated its ability to detect cancers in asymptomatic individuals with a positive predictive value of 60%, with 83.3% accuracy in detecting tumor location. Furthermore, we presented a case report to support further using SPOT-MAS as a complementary method to achieve early cancer detection and provide the opportunity for early treatment. Conclusions: Our study has demonstrated the clinical application of a multi-cancer blood test in a low- and middle-income country like Vietnam, where a nationwide cancer screening program is urgently needed but currently not available. Beyond detecting cancer signals, our test predicted the tumor location, allowing clinicians to fast-track the follow-up diagnostic and guide any necessary treatment. Keywords: liquid biopsy, ctDNA, clinical validation, prospective trial, cancer screening. Clinical trial information: NCT05227261 .
The role of natural language processing techniques versus conventional methods to gain ICI safety insights from unstructured EHR data.
Authors: Block Matthew Stephen , Barman Hannah , Venkateswaran Sriram , Del Santo Antonio Giuseppe , Yoo Unice , Silvert Eli , Chandler G Scott , Wagner Tyler , Mohindra Rajat
Published: August 2023

136

Background: Studies using International Classification of Diseases (ICD) codes have aimed to characterize the safety profile of cancer therapies in the Real-World Data setting, but this approach has limitations including an inability to illustrate patient journey and offer insights into drug-Adverse Event (AE) causality. Using data from a cohort of ~9000 patients treated with immune checkpoint inhibitors (ICI) at Mayo Clinic, we recently demonstrated the feasibility of applying Augmented Curation (AC), a natural language processing (NLP)-based innovation, on unstructured electronic health record (EHR) data to detect and characterize immune related AEs (irAEs). While the ability to identify and extract clinical details from EHRs has been previously demonstrated, our approach focuses on applying these techniques to identify implied textual causality of drug-event pairs. This study aims to build upon our prior findings and compare the accuracy, speed, and resource savings enabled by AC analysis versus manual review of patient notes. Methods: We compared the prevalence of adrenal insufficiency, colitis, and hypophysitis (A.C.H) among ICI patients at Mayo Clinic using ICD codes and AC which leverages SciBERT to perform scientific NLP tasks. AC models trained to identify drug-adverse event relationships were used to assess irAEs and subsequent treatments and demonstrated strong performance with F1 scores of 0.85. Manual curation of relevant clinical data, i.e. medications and adverse events, was employed to create a “gold standard” A.C.H. cohort. Time required for manual review compared to AC was documented for overall comparison. Corticosteroid/immunosuppressant use and ICI discontinuations were used as proxies of severity. Results: In our cohort, 540 unique patients experienced at least one of the A.C.H. irAEs. A.C.H patients were found to receive corticosteroids for their respective irAE 79% of the time and discontinued the ICI due to the irAE 7.7% of the time. 6.1% of Colitis patients were treated with a 2L immunosuppressant. Similar to the previous study, AC showed higher sensitivity, PPV and NPV compared to ICD codes alone within the A.C.H. cohort. Sentence extraction and entity classification using AC models on all 9,000-patients took ~10 minutes, whereas manual review of this cohort would take roughly 9 weeks (~10 minutes per patient). Conclusions: The results from this study reinforce that AC models are a valuable tool to comprehensively extract information and to impute relationships between entities, such as therapies and AEs. The AC models demonstrated better accuracy at a much greater speed compared to manual review of patient EHRs. Leveraging AC models provides the ability to manipulate unstructured clinical text married to structured EHR data at scale while minimizing need for manual curation.
Knowledge, attitude toward palliative care and associated factors among clinical nurses in Vietnam.
Authors: Thi Cuc Le , Minh Anh Duong , Quang Trung Truong
Published: August 2023

137

Background: Nurses who offer palliative care must be knowledgeable about several aspects of caring for advanced cancer patient. The concept of palliative care is not widely discussed in Vietnam, and there needs to be more data regarding the knowledge and attitude of the nurses. This study’s objectives were to (1) Describe the knowledge and attitudes about palliative care of nurses and (2) Identify related factors with knowledge and attitudes about palliative care among those nurses. Methods: A cross-sectional study was conducted among 118 nurses working in a University Hospital. The Palliative Care Quiz for Nursing (PCQN) and The Frommelt Attitude Towards Care of the Dying Scale (FATCOD) were used to measure the participants' knowledge and attitude toward Palliative care. The 34-item of PCQN used a ‘true/ false/don’t know’ format with possible scores ranging from 0 to 34. The FATCOD consists of 30 items, Positive items were scored from 1 (strongly disagree) to 5 (strongly agree). Possible scores ranged from 30 to 150. The Statistical Package for Social Sciences (SPSS) version 21 was used to analyze the data. The level of significance for all analyses was set at less than 0.05. Results: There were 118 nurses completed the questionnaire. Most participants were female (69.5%) and younger than 25 years (84.7%). Nearly two-thirds of nurses had graduate and postgraduate degrees (67.8%) and 62% of nurses had more than five years of working experience. 24% of nurses have received palliative care training, and 96% of nurses wanted to learn palliative care, 85% of nurses reported that palliative care is necessary for their work. Most of them (78%) had moderate palliative care knowledge; only 31% of the nurses had a positive attitude toward palliative care. A significant relationship was found between working experience and a positive attitude toward palliative care (p < 0.05). Conclusions: Nurses’ knowledge and attitude about palliative care were not high. Clinical nurses need more education to develop their palliative care knowledge and skills. Palliative care should be added to the curriculum for undergraduate students.
The preventive effects of early short-course corticosteroids on immune-related adverse events in non-small cell lung cancer patients receiving immune checkpoint inhibitors.
Authors: Huang Derek , Liao Bin-Chi , Cheng Ann-Lii , Yang James Chih-Hsin , Shen Ying-Chun
Published: August 2023

144

Background: Corticosteroid is effective in treating immune checkpoint inhibitor (ICI)-induced immune-related adverse events (irAEs). However, whether its earlier use prevents irAEs remains unknown. In real-world practice, non-small cell lung cancer (NSCLC) patients receiving combined immunochemotherapy are often given corticosteroids right after ICI injection to reduce subsequent chemotherapy-related adverse events. It is thus an ideal model to examine whether this earlier use of corticosteroid also reduce irAEs following immunotherapy. Methods: NSCLC patients receiving at least one cycle of ICI with or without chemotherapy were enrolled. Patients receiving ICI with corticosteroid corticosteroid premedication exposure were categorized as “corticosteroid group (CS)”, whereas patients receiving ICI without corticosteroids premedication exposure were categorized as “non-corticosteroid group (non-CS)”. Frequency of irAEs prompting systemic corticosteroid or leading to ICI discontinuation were compared between the two groups. Exploratory survival analysis was performed. Results: Among 252 eligible patients, 137 patients were categorized as CS group, and 115 patients as non-CS group. 21.9% of patients in the CS group and 30.4% of patients in the non-CS group developed irAEs prompting systemic corticosteroid use (Odds ratio [OR], 0.64; 95% confidence interval [CI], 0.35 to 1.18; p=0.15). 5.8% of patients in the CS group and 15.7% of patients in the non-CS group developed irAEs leading to ICI discontinuation (OR, 0.34; 95% CI, 0.12 to 0.85; p=0.013). In the exploratory survival analysis, early short-course corticosteroids was not associated with a higher risk for death in first-line patients (hazard ratio [HR], 1.06; 95% CI, 0.56–2) or patients receiving immunochemotherapy (HR, 0.72; 95% CI, 0.37–1.45). Conclusions: Early short-course corticosteroids following each ICI injection may reduce the rate of irAEs that leads to ICIs discontinuation. The use of prophylactic corticosteroids on irAEs in cancer patients receiving ICIs should be evaluated in future prospective studies. [Table: see text]
Role of microphthalmia-associated transcription factor in uveal melanoma and its association with clinicopathological parameters.
Authors: Jha Jayanti , Singh Mithalesh Kumar , Singh Lata , Neiwete Lomi , Pushker Neelam , Sen Seema , Kashyap Seema
Published: August 2023

153

Background: High melanin content could lead to high metastatic potential in Uveal Melanoma (UM). In the Asian population, Microphthalmia-Associated Transcription Factor (MITF) regulates the melanogenesis pathway and activates Silver Protein (SILV) for eumelanin synthesis. MITF also stimulates the hypoxia–inducible factor 1-alpha (HIF-1α) gene that regulates hypoxia around the tumor microenvironment. Although their oncogenic potential has been observed in a variety of malignancies, MITF and SILV have not been investigated in UM in the Asian population. Therefore, our study aimed to detect the prognostic significance of MITF, SILV, and HIF1-α gene/protein expression levels in UM patients. Methods: Immunohistochemistry of MITF, SILV & HIF-1 α was performed on 82 UM tissue samples. Western blot of all three markers was carried out on representative cases. The mRNA expression level was done by qRT-PCR in 70 fresh UM cases. Cox proportional hazard model and log-rank test were used to determine the prognostic outcome of these markers. Results: MITF and SILV proteins were expressed in 56% and 70% of cases, respectively. High pigmentation, BAP1 loss, and HIF-1α expression were statistically correlated with MITF and SILV protein expression. Upregulation of both genes was found in more than 50% of cases at the mRNA level. This was also statistically significant with high pigmentation and HIF-1α mRNA expression. High expression of MITF protein showed reduced disease-free survival. Conclusions: Our study highlighted the fact that MITF and SILV could be potential biomarkers in UM development. Hence, it might play a key role in future therapeutic target.
Establishment and effect evaluation of a hierarchical pharmacological monitoring model for immune checkpoint inhibitors.
Authors: Zhu Yaning , Zhāng Peng
Published: August 2023

159

Background: To establish a standardized pharmacy service model for PD-1 monoclonal antibodies through a case study of the practice of full pharmacy service for immune checkpoint inhibitors and to explore the effect of clinical pharmacists' participation in the full pharmacy service for PD-1 monoclonal antibodies. Methods: Patients were graded according to age, pathological stage, Carlson co-morbidity index grading and different treatment stages (preoperative neoadjuvant, postoperative adjuvant and advanced first-line, second-line and third-line or above), whether they had concomitant autoimmune diseases and combination drug use (monotherapy, combination chemotherapy, combination targeted or anti-angiogenic drugs, combination chemotherapy + targeted/anti-angiogenic drugs) to establish PD-1 The effect of this pharmacy service model was evaluated by using the immunotherapy treatment of 132 patients in Shaanxi Provincial People's Hospital who were pharmacologically monitored by clinical pharmacists. Results: 132 patients, 91 males and 41 females, 7 patients aged ≥ 70 years with stage IV tumor and Carlson co-morbidity index ≥ 9 scores were subjected to special grade pharmacological monitoring, 1 patient developed immune myocarditis, 1 patient developed immune pneumonia and reactive capillary hyperplasia, which improved after treatment with methylprednisolone, age < 70 years, stage IV tumor, Carlson Primary pharmacological monitoring was performed in 13 patients with co-morbidity index ≥9 points, of which 10 cases (76.9%) had adverse reactions, 3 cases had pulmonary infections and discontinued, 2 cases had severe thrombosis of grade 3 or higher leading to discontinuation, and the others were hyperthyroidism, hypothyroidism, hypocorticism, etc. Secondary monitoring was performed in the other 112 patients, of which 11 cases (9.8%) had adverse reactions The other cases were immune enteritis, immune encephalitis and immune myocardial injury, and most of the adverse reactions occurred in the 5th cycle after drug administration. Conclusions: By establishing a hierarchical pharmacological monitoring model; patients aged <70 years, stage IV tumors, and Carlson co-morbidity index score ≥9 are at high risk for adverse reactions to immunotherapy, and pretreatment of these patients in advance can ensure the safety of patients' medication, improve medication compliance, and improve patients' quality of life.
Clinical outcomes of soft tissue sarcoma in the Philippines: A single-center experience.
Authors: Maaño Omar Paningbatan , Gorospe Agnes Evangelista , Pascual-Panganiban Anna Marie Mangune
Published: August 2023

160

Background: Soft-tissue sarcomas (STS) are a heterogeneous group of uncommon tumors that account for less than 1 percent of all adult malignant tumors. Data are scarce in the Asia-Pacific region, especially in the Philippines. This study aims to evaluate the epidemiology and clinical outcomes of STS from a private tertiary hospital in the Philippines. Methods: All adult patients treated at St. Luke’s Medical Center (SLMC), Quezon City and Global City, between January 2010 and December 2020 were reviewed. Continuous variables are described in median and categorical variables are described in count and percentage. Kaplan-Meier curves for OS and RFS were compared by the Log-Rank test. Results: One hundred eighty-seven patients diagnosed with STS were eligible for the study. The median age at diagnosis was 53 years old; the majority were male (54.55%). The most common histologic subtypes were liposarcoma (19.79%), pleomorphic sarcoma, undiff (16.58%), and leiomyosarcoma (11.76%). Most were diagnosed with localized disease (90.9%), with the lower extremities (44.39%) as the most common primary site. The median tumor size was 10.3 cm, primarily high grade (46.52%). Nodal involvement on diagnosis was 4.28%. Twelve patients (6.42%) presented with de novo mets; lung (45%) was the most common site. The majority had surgery (81.82%) on the primary tumor, with 56.86% achieving R0. Eighty patients (42.78%) had radiotherapy; the majority were given post-operatively (N=60). Sixty-three patients (33.68%) received systemic therapy. Out of 170 patients with localized disease, 70 (40%) had disease recurrence, mostly local recurrence (57.14%). The 3-year OS and RFS were 58.67% and 55.20%, respectively, for the entire cohort; for localized disease was 95.06%. There was a statistical difference in OS between distant vs local recurrence (23.28% vs 49.11%) (p<0.001), nodal involvement (p=0.041), surgery (p<0.001), and radiotherapy (p=0.001). Conclusions: Most STS seen in SLMC is localized disease but with lower rates of resection than in other countries in the Asia-Pacific region. The histological subtype and primary anatomical site are similar to other data. The low survival rate may be attributed to the site of recurrence, nodal involvement, and treatment pattern received.
A study on the correlation of GDF15 with cancer cell invasion and poor prognosis in gallbladder cancer.
Authors: Joo Mina , Lee Hyo Jin , Kim Jin Man
Published: August 2023

167

Background: Growth differentiation factor 15 (GDF15) is a member of the TGF-β superfamily and has been found to be expressed in various human cancers. This study investigated the role of GDF15 in gallbladder cancer and its underlying molecular mechanisms. Methods: We examined immunohistochemical staining to evaluate the expression of GDF15 in 57 cases of gallbladder cancer using a tissue microarray, and clinic-pathological parameters were analyzed. In addition, we established a stable cell line overexpressing GDF15 using NOZ and OCUG-1 gallbladder cancer cell lines. The successful overexpression of GDF15 was confirmed using RT-PCR and western blot analysis. Migration and invasion assays were performed using transwell plates coated with collagen or matrigel, and cell motility was analyzed using a wound healing assay. We also performed western blot analysis to detect the expression levels of various proteins associated with cell proliferation, migration, and invasion. Results: High GDF15 expression was significantly associated with pathologic T stage ( P = 0.063), differentiation ( P = 0.062), perineal invasion ( P = 0.059) and lymphatic invasion ( P = 0.008). High GDF15 expression has also been associated with poor prognosis. Overexpression of GDF15 significantly enhanced wound healing, cell migration, invasion, and motility in comparison to controls and regulated the expression of related proteins. Our results indicate that GDF15 enhances the migratory, invasive, and motility abilities of NOZ and OCUG-1 cells in vitro and is involved in poor prognosis and overall survival of gallbladder cancer patients. Conclusions: This study implies that GDF15 could serve as a potential therapeutic target in gallbladder cancer.
Deep learning based on preoperative MR to differentiate germinomas from nongerminomatous cell tumors.
Authors: Li Yanong
Published: August 2023

19

Background: Intracranial germ cell tumors (iGCTs) are highly malignant brain tumors that predominantly occur in children. Two types of iGCTs exist: germinomas (GEs) and non-germinomatous germ cell tumors (NGGCTs), each having different treatments and prognoses. However, predictive biomarkers for differentiation are limited. Methods: This multicenter Development-validation set study included patients with iGCTs with pathology-confirmed for the developed dataset (n = 280), which was split into training (n = 200) and testing sets (n= 80), and three independent validation sets (n = 64), respectively. Patients were included between January 2010 and December 2021. We developed a DL model based on 3D nnU-Net and preoperative T2-weighted images to differentiate GE from NGGCT, and we compared the model performance with the diagnoses made by five physicians of different majors and experiences with and without referring to the DL model’s output. Data analysis was performed from February 2021 to May 2022.We calculated the diagnostic performances of the model and physicians using the area under the curve (AUC), accuracy, sensitivity, and specificity. Results: The DL pipeline showed an average AUC of 0.837 in the testing set and three independent validation sets, superior to that using conventional information alone (combine with MR features and clinical information, AUC=0.768, p=0.009). The physicians’ diagnoses showed an average AUC of 0.695 without reference to the DL output and 0.842 concerning the DL output in the testing and prospective internal validation sets, with a 21.15% improvement (p=0.014). Conclusions: We developed and validated a DL model using a large dataset to accurately differentiate GE from NGGCT using preoperative T2-weighted images, which is relatively easily incorporated into the workflow of clinical diagnosis at minimal additional cost, and may enhance precision therapy.
A comprehensive survey of tumor mutation burden (TMB) using the AACR GENIE cbioportal database: Pathogenesis of NTRK and RET fusion (NTRK+/RET+) positive colorectal (CRC).
Authors: Arter Zhaohui , Lee Alexandria TM , Nagasaka Misako , Ou Sai-Hong Ignatius
Published: August 2023

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Background: Receptor tyrosine kinase fusion (RTK+) has been identified in colorectal carcinoma (CRC). Tumor agnostic treatment has been approved in NTRK fusion ( NTRK+) and RET fusion ( RET+) positive solid tumor. However, overall response rate (ORR) was the lowest among entrectinib-treated NTRK+ CRC (20%, 2/10) and selpercatinib treated RET+ CRC (20%, 2/10) among all NTRK+ and RET+ solid tumors respectively. Methods: We surveyed all 58 human RTKs to identify RTK fusions in CRC and RET and NTRK fusions in other solid tumors using AACR GENIE cbioportal public version 13.0. We abstracted and compared the tumor mutation burden (TMB) of these fusions from the cbioportal database. Patient and tumor characteristics were also abstracted. Results: Among the 14812 unique CRC patients identified in the AACR GENIE cbioportal, a total of 153 unique RTK fusions were identified (44 with known fusion partners, 109 with intragenic rearrangement) in 27 out of the total 58 human RTKs. The most common RTK fusions in CRC were in FGFR1 (N = 23), EGFR (N = 21), ERBB2, NTRK1, RET, FGFR2 (N = 10 each), FLT1 and FLT3 (N = 9 each), FLT4 and ALK (N = 7 each). Considering only samples with identified fusion partners, the mean TMB was 66.6 +/-15.8 (mt/MB) for NTRK+ CRC (N = 9), and 35 +/-11.5 for RET+ CRC (N = 4), which were significantly higher when compared to mean number of 6.2 +/- 5.4 of TMB for all other RTK+ CRC (ALK, EGFR, FGFR1/2, ERBB4, FLT1/3/4, LMKT2, MET, NTRK2, PDGFR-b, ROS1) (N = 30, P< 0.05). Furthermore, NTRK+ CRC harbored significantly higher TMB than RET+ CRC (P = 0.003). The mean TMB was 4.0 +/- 1.9 for RET+ NSCLC (N = 65), 2.6 +/- 1.6 for RET+ Thyroid cancer (N = 52), which were both significantly lower than RET+ CRC. Mean TMB was 3.1 +/- 1.7 for NTRK+ glioma (N = 21), 3.3 +/- 1.7 for NTRK+ thyroid cancer (N = 21), 6.5+/-5.1 for NTRK+ Melanoma (N = 8), 5.9 +/- 3.4 for NTRK+ NSCLC (N = 7), 5.1 +/- 1.2 for NTRK+ breast cancer (N = 7) all of them were significantly lower than the mean TMB of NTRK+ CRC. 1482 (10.0%) patients with CRC had their MSI status reported. 3 out of 3 NTRK+ CRC patients with known MSI status were all MSI-H (100%). 12 out of 12 non-NTRK/non-RET RTK+ CRC patients were MSI-S. Conclusions: In this comprehensive survey of human RTK fusions in CRC, NRTK+ and RET+ CRC harbor significantly higher TMB compared to other RTK+ CRC or to other NTRK+/RET+ solid tumors. Limited data showed NTRK+ CRC were all MSI-H. NTRK+ and RET+ CRC are distinct molecular subtypes of CRC with unique pathogenesis from all other NTRK+ or RET+ solid tumors. We hypothesize that NTRK+/RET+ CRC may benefit from pembrolizumab that has been approved for histologic agnostic high TMB tumors rather than RET or NTRK tyrosine kinase inhibitors (low ORR in CRC) that also have histological agnostic indications.
Comprehensive analysis of acetylation-related genes for the prognosis and immunotherapy response of gastric cancer.
Authors: Liu Yi , Wang Jianhua
Published: August 2023

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Background: Although clinical researchers have made great progress in the treatment of gastric cancer, the overall survival time of gastric cancer patients remains unfavorable,It has been reported that HDAC1 is a prognostic marker for survival. However, the relationship between acetylation modification and the prognosis and treatment of gastric cancer has not been elaborated so far. Therefore, we carried out a systematic study and hope to provide novel therapeutic targets. Methods: We obtained the RNA sequencing data of GC patients and the corresponding clinical features from GEO database. T-test was performed to analyze the difference in expression of acetylation-related genes in normal and tumor samples from TCGA-STAD dataset.Using median expression as the threshold, univariate cox regression was performed to analyze the prognostic differences in overall survival (OS) for each acetylation-related gene. ssGSEA was utilized to analyze the percentage of infiltration of 28 immune cells in different clusters. Subsequently, we performed functional enrichment analysis of the differential genes using DAVID.used TIDE to analyze the effect of immune checkpoint inhibition. In addition, we compared the differences in TIDE scores across scoring subgroups. Results: By comparing 32 normal samples and 362 tumor samples in the TCGA dataset, we found that most acetylation-related genes are differentially expressed.most of the KAT genes were amplified more frequently than the deletion frequency, especially KAT2A and ESC1, while the deletion frequency of HDAC4 was high.CREBBP and KAT6A genes were mutated with high frequency.The results of acetylation-related gene clustering were divided into two subgroups (KAT-KDAC-cluster 1 and KAT-KDAC-cluster 2), Cluster 1 was mainly enriched in processes such as mismatch repair and homologous recombination during DNA replication, and cluster 2 was mainly enriched in calcium signaling, insulin signaling pathway and actin cytoskeleton regulation.We filtered out 9 genes most associated with GC were screened by random forest, and 2 of them were found to be unrelated to patient prognosis by univariate analysis, resulting in 7 genes, including FERMT2, CALD1, TGFBII, PPP1R14A, PPPIR3C, ADAMTS1, and RBPMS2.and KAT-KDAC scores were calculated.KAT-KDAC score group had lower TIDE scores, predicting better immune efficacy for patients in the low-KAT-KDAC score group. Conclusions: Expression of acetylation-related genes affects the prognosis of gastric cancer.
Prognostic analysis of postoperative pathological microvascular invasion in hepatocellular carcinoma and the effect of surgical margin on prognosis.
Authors: Chen Huanwei
Published: August 2023

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Background: To analyze the impact of different MVI grades and surgical margins on patient survival through analyzing the presence of microvascular invasion (MVI) after liver resection of hepatocellular carcinoma (HCC). Methods: The clinical and follow-up data of 513 HCC patients who underwent hepatectomy in our department from January 2016 to December 2020 were analyzed retrospectively. All the patients signed the informed consent form, complying with the medical ethics regulations. Risk factors of MVI in patients with HCC were analyzed by univariate and multivariate analysis, and effect of different MVI grades on postoperative complications was explored. The effects of different MVI grades and different surgical margins on tumor-free survival and overall survival were also analyzed. Results: There were 332 cases in M0 group, 123 cases in M1 group and 58 cases in M2 group. Univariate analysis showed that tumor diameter, tumor number, CNCL stage and alpha-fetoprotein were risk factors for MVI in patients with HCC, and multivariate analysis showed that tumor maximum diameter, tumor number and CNLC stage were independent influencing factors for MVI. There was no significant difference in the incidence of postoperative complications among different groups. The 1-year, 2-year, 3-year disease-free survival rate of M0 group was 79.6%, 71.0%, 63.4%, which was significantly higher than that in M1 group (59.6%, 48.0%，43.3%) and M2 group (31.0%, 27.5%, 25.2%). The 1-year, 2-year, 3-year overall survival rate of M0 group was 97.3%, 88.2%, 84.6%, which was significantly higher than that in M1 group (87.0%, 71.5%, 66.1%), and M2 group (79.3%, 61.9%, 52.6%),respectively. In the aspect of surgical margin, in MVI negative group, the disease-free survival rate of wide margin resection for 1-year, 2-year, 3-year was 82.6%, 70.7%, 65.4%, while that of narrow margin resection was 79.4%, 64.7% and 60.5% (p=0.322).The 1-year, 2-year, 3-year overall survival rate of patients who received wide margin resection was 97.5%, 89.6%, 85.2%, while that of patients who received narrow margin resection was 97.1%, 86.0%，82.8%. (p= 0.822). In the MVI positive group, the 1-year, 2-year and 3-year disease-free survival rate was 58.1%, 45.4%, 40.3% in the wide margin group and 42.9%, 37.3%, 36.1% in the narrow margin group (p=0. 044). The 1-year, 2-year, 3-year overall survival rate of the wide margin group was 88.8%, 71.9%, 64.3%, which was higher than that of the narrow margin group, 82.6%, 64.8%, 61.0% (p = 0.032). Conclusions: Tumor size, number and stage are independent risk factors for MVI positive patients.The higher the MVI grade, the worse the prognosis.In patients with MVI, the long-term prognosis of patients with wide margin is better than that of patients with narrow margin. Therefore, for patients with high risk of MVI before operation, wide margin should be selected as far as possible.