Individualized Treatment Design Research Articles

Pathway-based stratification of gliomas uncovers four subtypes with different TME characteristics and prognosis.

Increasing evidences have found that the interactions between hypoxia, immune response and metabolism status in tumour microenvironment (TME) have clinical importance of predicting clinical outcomes and therapeutic efficacy. This study aimed to develop a reliable molecular stratification based on these key components of TME. The TCGA data set (training cohort) and two independent cohorts from CGGA database (validation cohort) were enrolled in this study. First, the enrichment score of 277 TME-related signalling pathways was calculated by gene set variation analysis (GSVA). Then, consensus clustering identified four stable and reproducible subtypes (AFM, CSS, HIS and GLU) based on TME-related signalling pathways, which were characterized by differences in hypoxia and immune responses, metabolism status, somatic alterations and clinical outcomes. Among the four subtypes, HIS subtype had features of immunosuppression, oxygen deprivation and active energy metabolism, resulting in a worst prognosis. Thus, for better clinical application of this acquired stratification, we constructed a risk signature by using the LASSO regression model to identify patients in HIS subtype accurately. We found that the risk signature could accurately screen out the patients in HIS subtype and had important reference value for individualized treatment of glioma patients. In brief, the definition of the TME-related subtypes was a valuable tool for risk stratification in gliomas. It might serve as a reliable prognostic classifier and provide rational design of individualized treatment, and follow-up scheduling for patients with gliomas.

Dosimetric Analysis of Limiting Pelvic Bone Dose in Intensity-modulated Radiotherapy for Cervical Cancer

Numerous studies have indicated the significant importance of pelvic dose in the radiotherapy process for cervical cancer patients. However, research on the actual pelvic bone dose in the treatment of cervical cancer patients using different techniques is currently relatively limited. In this study, we selected 50 postoperative cervical cancer patients. For each patient, three treatment plans with pelvic dose constraints were designed: sIMRT, VMAT, and HT. Statistical analysis was conducted on the target area and organ at risk parameters of the three groups of plans. The results indicate that all three treatment plans meet the clinical requirements. Regarding organs at risk, compared to the sIMRT and VMAT groups, the HT group showed a reduction of 11.85% and 11.07%, respectively, in V40 of bladder. Additionally, compared to the sIMRT and HT groups, the VMAT group exhibited a reduction of 14.94% and 9.53%, respectively, in V10 of pelvic bone. Furthermore, compared to the sIMRT and HT groups, the VMAT group showed a reduction of 10.76% and 6.75%, respectively, in V20 of pelvic bone, and these differences were also statistically significant (t = 21.630, t = –16.621, P < 0.05). In summary, individualized treatment design can be conducted in clinical practice based on the specific conditions of patients.

Advanced care planing and end of life decisions - the geriatricians' view

Medical progress and the increasing desire for self-determination, even in the most difficult life situations, as well as the associated increasing possibilities of influencing life and dying lead to possibilities but also obligations for individual treatment design. Especially at the end of life, the desire for provision is great and many decisions need to be made in advance or by proxy. In daily dealings with sick or seriously ill people at the end of their lives, it is very helpful if appropriate advance directives have been made and the patient's wishes can be implemented simply and clearly. With the possibility of advance planning for the end of life (Advance Care Planning (ACP)), there is a precautionary and planning concept that will hopefully be used more and more in the future.

Antidepressant Effects of a Multimodal Group Therapy Program for Mild Dementia: A Retrospective Evaluation of Clinical Routine Data.

The multimodal CORDIAL treatment concept for mild dementia, combining cognitive rehabilitation, cognitive behavioral and humanistic psychology interventions, has proven its feasibility and demonstrated a reduction of depressive symptoms in individual dyadic/triadic settings. We investigate antidepressant effects of an adapted group-based CORDIAL program in clinical routine care. During 2013 and 2017, 51 outpatients with mild dementia (45% female, mean age 72.4 years, 67% Alzheimer's dementia, mean MMST 24.8) periodically received a modified CORDIAL group treatment as part of our regular outpatient care. Treatment comprised 10 bi-weekly sessions, partly involving caregivers. Systematic pre- and post-treatment assessments of clinical routine data were evaluated retrospectively (median time-interval of 6.6 months). Depressive symptoms as measured by the Geriatric Depression Scale significantly decreased over time (p = 0.007, Cohen's d = 0.39), and irrespective of gender. Patients with longer disease duration before treatment start showed significantly higher initial levels of depressive symptoms (p = 0.044), followed by a reduction to a level of those with shorter disease duration (ns). Most secondary outcomes (cognitive symptoms, disease severity, quality of life, caregiver burden) remained unchanged (ns), while competence in activities of daily living declined from pre- to post-measurement (p = 0.033). A group-based CORDIAL treatment is feasible in a clinical routine setting and demonstrated antidepressant effects comparable to those of the individual treatment design, further suggesting its implementation in regular care. Future trials might also investigate its potentially preventive effects by reducing depressive symptoms in pre-dementia stages, even at a subsyndromal level.

Establishment and validation of a predictive model for neurogenic urinary tract injury in children

Objective: To establish a predictive model for upper urinary tract damage in children with neurogenic bladder and verify its efficacy. Methods: From January 2011 to December 2021, 143 children with NB in the Children's Hospital of Chongqing Medical University and 84 children with NB in the First Affiliated Hospital of Zhengzhou University were selected as the research objects. The former is set as the training set and the latter is set as the validation set, and the general parameters of the two are compared. The independent risk factors of upper urinary tract damage in children with NB were screened out by Lasso regression, and multivariate logistic regression analysis and a nomogram prediction model was established. The models were validated internally and externally on the training set and validation set, respectively, and the area under the receiver operating curve (ROC) was used to verify the accuracy of the model. Results: A total of 227 children with NB were included in this study, including 121 males and 106 females, aged (10.2±3.8) years. There was no significant difference in other parameters except age between the training set and validation set (all P>0.05); Lasso regression and multivariate logistic regression analysis showed that detrusor leakage point pressure (DLPP) ≥ 40 cmH2O (OR=4.76, 95%CI: 2.01-11.26, 1 cmH2O=0.098 kPa), overactive bladder (OAB) (OR=3.08, 95%CI: 1.34-7.04), bladder compliance (BC)<20 ml/cm H2O (OR=3.65, 95%CI: 1.41-9.47), history of previous urinary tract infection (OR=2.73, 95%CI: 1.09-6.81), and abdominal pressure/other voiding patterns (OR=2.86, 95%CI: 1.20-6.82) were risk factors for upper urinary tract damage in children with NB (all P<0.05). The above parameters were used to establish a nomogram model of upper urinary tract damage in children with NB. The internal and external validation results show that the AUC values for the training and validation sets were 0.84 (95%CI: 0.77-0.91) and 0.86 (95%CI: 0.79-0.94), respectively. Conclusion: The prediction model of upper urinary tract damage in children with NB constructed in this study has high discrimination, accuracy and clinical applicability, which can help clinicians identify high-risk patients and make individualized treatment design for these patients.

Pan-cancer analysis of the prognostic and immunological role of ANLN: An onco-immunological biomarker.

Anillin actin-binding protein (ANLN) is crucially involved in cell proliferation and migration. Moreover, ANLN is significantly in tumor progression in several types of human malignant tumors; however, it remains unclear whether ANLN acts through common molecular pathways within different tumor microenvironments, pathogeneses, prognoses and immunotherapy contexts. Therefore, this study aimed to perform bioinformatics analysis to examine the correlation of ANLN with tumor immune infiltration, immune evasion, tumor progression, immunotherapy, and tumor prognosis. We observed increased ANLN expression in multiple tumors, which could be involved in tumor cell proliferation, migration, infiltration, and prognosis. The level of ANLN methylation and genetic alteration was associated with prognosis in numerous tumors. ANLN facilitates tumor immune evasion through different mechanisms, which involve T-cell exclusion in different cancer types and tumor-infiltrating immune cells in colon adenocarcinoma, kidney renal clear cell carcinoma, liver hepatocellular carcinoma, and prostate adenocarcinoma. Additionally, ANLN is correlated with immune or chemotherapeutic outcomes in malignant cancers. Notably, ANLN expression may be a predictive biomarker for the response to immune checkpoint inhibitors. Taken together, our findings suggest that ANLN can be used as an onco-immunological biomarker and could serve as a hallmark for tumor screening, prognosis, individualized treatment design, and follow-up.

Analysis of immune subtypes based on immunogenomic profiling identifies prognostic signature for cutaneous melanoma

Skin cutaneous melanoma (SKCM) is the most invasive form of skin cancer with poor prognosis. Growing evidence has demonstrated that tumor immune microenvironment plays a key contributing role in tumorigenesis and predicting clinical outcomes. The aim of this study was to recognize immune classification and a reliable prognostic signature for patients with SKCM. By using single-sample gene set enrichment (ssGSEA) and hierarchical clustering analyses, we evaluated the immune infiltration landscape of SKCM afflicted patients from The Cancer Genome Atlas (TCGA) dataset and named two SKCM subtypes: Immunity-high and Immunity-low. The Immunity-high subgroup was characterized by up-regulation of immune response and favorable survival probability. Seven candidate small molecule drugs which potentially reverse SKCM immune status were identified by using Connectivity map (CMap) database. A prognostic five-immune-associated gene (IAG) signature consisting IFITM1, TNFSF13B, APOBEC3G, CCL8 and KLRK1 with high predictive value was established using the LASSO Cox regression analysis in training set, and validated in testing set as well as Gene Expression Omnibus (GEO) external validation cohort (P < 0.05). Lower tumor purity and active immune-related signaling pathways were obviously presented in low-risk group. Furthermore, a novel composite nomogram based upon the five-IAG signature and other clinical parameters was built with excellent calibration curves. Collectively, comprehensively characterizing the SKCM subtypes based upon immune microenvironment landscape and development of a survival-related IAG signature may provide a promising avenue for improving individualized treatment design and prognosis prediction for patients with SKCM.

BDNF Met allele Is Associated With Lower Cognitive Function in Poststroke Rehabilitation

Background and purpose. The identification of a genetic role for cognitive outcome could influence the design of individualized treatment in poststroke rehabilitation. The aim of this study is to determine whether brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is independently associated with poststroke functional outcome. Methods. A total of 775 stroke patients with genomic data were identified from the Partners HealthCare Biobank, which contains a large number of genotypes from Biobank’s consented patients. Of 775 stroke patients who met the inclusion/exclusion criteria, 86 were enrolled. Functional outcomes were assessed using the Functional Independence Measure scores at the time of admission and discharge. Logistic and linear regression models adjusted for covariate variables, including age, sex, and medical conditions, were used to evaluate the association between BDNF Val66Met and functional outcome. Results. We detected a significant correlation between Met alleles and lower cognitive function at discharge in both ischemic and hemorrhagic stroke patients. Genotyping findings confirmed that BDNF Met allele frequency was higher in contrast to Val/Val allele frequency in lower cognitive functional recovery. Furthermore, after adjusting for covariate variables, BDNF Met alleles were found to be associated with lower cognitive outcome [P = .003; odds ratio (OR) = 5.95 (1.81-19.52)] and recovery [P = .006; OR = 3.16 (1.4-7.15)], especially with lower problem solving, expression, and social recovery in all stroke patients. Conclusions. Met allele carriers exhibited impaired poststroke cognitive function. The BDNF genotype may be a useful predictor of cognitive function in inpatient poststroke rehabilitation.

Pathogen-based precision medicine for drug-resistant tuberculosis.

The implementation of next generation sequencing techniques, such as whole-genome sequencing (WGS), in tuberculosis (TB) research has enabled timely, cost-effective, and comprehensive insights into the genetic repertoire of the human pathogens of the Mycobacterium tuberculosis complex (MTBC). WGS data allow for detailed epidemiological analysis based on genomic distance of the MTBC strains under investigation, e.g., for tracing outbreaks; it can accelerate diagnostics by predicting drug resistance from a mutation catalogue (Fig 1). Indeed, specific mutations even permit predictions on the possible clinical treatment course and outcome [1–4]. Open in a separate window Fig 1 Principle of pathogen-tailored individualized treatment design. (A) Mutations are obtained from a whole-genome sequencing reference mapping approach that can be also transferred into a cgMLST for molecular outbreak surveillance. (B) Individual mutations are further interpreted towards their biological phenotype employing a validated consensus mutation catalogue. (C) When canonical and/or high-level resistance-conferring mutations are present, this drug should not be used. However, mutations associated with a moderate or intermediate resistance level may allow the use of drugs at increased doses. Moreover, mutations can be used to predict different treatment outcomes. Thus, by also considering phylogenetic benign mutations that do not confer resistance, a comprehensive molecular drug susceptibility profile could be inferred for a pathogen-tailored individualized treatment regimen in the future. cgMLST,core genome multilocus sequencing type; TB, tuberculosis.

Patients’ experiences of a computerised self-help program for treating depression – a qualitative study of Internet mediated cognitive behavioural therapy in primary care

Objective: The objective of this study was to explore primary care patients’ experiences of Internet mediated cognitive behavioural therapy (iCBT) depression treatment.Design: Qualitative study. Data were collected from focus group discussions and individual interviews.Setting: Primary care.Method: Data were analysed by systematic text condensation by Malterud.Subjects: Thirteen patients having received iCBT for depression within the PRIM-NET study.Main outcome measures: Analysis presented different aspects of patients’ experiences of iCBT.Results: The informants described a need for face-to-face meetings with a therapist. A therapist who performed check-ups and supported the iCBT process seemed important. iCBT implies that a responsibility for the treatment is taken by the patient, and some patients felt left alone, while others felt well and secure. This was a way to work in privacy and freedom with a smoothly working technology although there was a lack of confidence and a feeling of risk regarding iCBT.Conclusion: iCBT is an attractive alternative to some patients with depression in primary care, but not to all. An individual treatment design seems to be preferred, and elements of iCBT could be included as a complement when treating depression in primary care. Such a procedure could relieve the overall treatment burden of depression.Key pointsInternet mediated cognitive behavioural therapy (iCBT) can be effective in treating depression in primary care, but patients’ experiences of iCBT are rarely studied• Most patients express a need for human contact, real-time interaction, dialogue and guidance when treated for depression.• The patient’s opportunity to influence the practical circumstances about iCBT is a success factor, though this freedom brings a large responsibility upon the receiver.• An individual treatment design seems to be crucial, and elements of iCBT could be included as a complement to face-to-face meetings.

Functional Connectivity in the Normal and Injured Brain

The brain is neither uniform nor composed of similar modules but is rather a mosaic of different and highly interconnected regions. Accordingly, knowledge of functional connectivity between brain regions is crucial to understanding perception, cognition, and behavior. Functional connectivity methods estimate similarities between activity recorded in different regions of the brain. They are often applied to resting state activity, thus providing measures that are by nature task independent. The spatial patterns revealed by functional connectivity are not only shaped by the underlying anatomical structure of the brain but also partially depend on the history of task-driven coactivations. Inter-subject differences in functional connectivity may, at least to some degree, underlie variability observed in task performance across healthy subjects and in behavioral impairments in neurological patients. In this respect, recent studies have demonstrated that behavioral deficits in patients with brain injury are not only due to local tissue damage but also due to altered functional connectivity among structurally intact regions connected to the damaged site. Studies based on functional connectivity have the potential to advance basic understanding of how brain lesions induce neuropsychological syndromes. Furthermore, they may eventually suggest improved rehabilitation strategies for patients with brain injury, through the design of individualized treatment and recovery protocols.

Assessment of a passive immunity mouse model to quantitatively analyze the impact of neutralizing antibodies on adeno-associated virus-mediated gene transfer

Adeno-associated viruses (AAVs) are common infective agents of primates. As such, healthy primates carry a large pool of AAV-specific neutralizing antibodies (NAbs), which inhibit AAV-mediated gene transfer therapeutic strategies. Thus, a clinical method to screen patient candidates for AAV-specific NAbs prior to treatment, especially with the frequently used AAV8 capsid component, will facilitate individualized treatment design and enhance therapeutic efficacy. In this study, we evaluated the efficacy and sensitivity of a passive immunity mouse model to quantitatively assess anti-AAV8 NAb titers, as compared to an in vitro immunoassay. The passive transfer model was established in C57BL/6 mice by tail vein injection of pre-defined sera from 23 male rhesus monkeys. The mice were then administered low dose (3e10 GC/mouse) self-complementary (sc) AAV8. The in vitro NAb assay indicated that 69.57% of the rhesus donors had pre-existing anti-AAV8 NAb. The in vivo NAb assay, however, was better able to detect low NAb titer (≤1:5), which can mediate neutralization in vivo. Indeed, 17 rhesus donors (74.0%) had pre-existing anti-AAV8 neutralization by in vivo NAb assay. Our findings indicated that the in vivo NAb assay is superior to the in vitro assay for detecting low NAb titers.

Paediatric salivary gland cancer in Finland

ObjectivesWorldwide, only 5% of all salivary gland tumours are reported in children and 35–50% of these are malignant. According to the Finnish Cancer Registry, 15 children were diagnosed with salivary gland cancer (SGC) during 1990–2009 in Finland. There are no previous studies available on the histopathology, treatment, and survival of patients with these rare malignancies in Finland. MethodsRetrospective patient and tumour data covering the past 20 years were retrieved from the five University Hospitals in Finland. Ten paediatric SGC patients with a median age of 14 years (range, 9–19 years) and with available adequate patient data were included. The series comprised four boys and six girls. Follow-up time varied from five months to 14 years. ResultsTwo patients had a history of a previous malignancy. The majority of cases had a parotid gland cancer (7/10), and mucoepidermoid carcinoma was the most common histological subtype (5/10). All patients presented with Stage I–II disease and were treated surgically with curative intent. One patient with a Stage I mucoepidermoid carcinoma of the parotid gland received postoperative radiotherapy. No recurrences were encountered and all patients were free of disease at the last follow up. ConclusionsThe individual treatment design for paediatric SGC should follow consistent treatment strategies. All patients in the present study had low-grade tumours with a favourable prognosis. Since paediatric SGC is infrequent worldwide, the diagnostics, treatment, and follow up should be centralized in multidisciplinary Head and Neck Centres.

Balancing Between Empirically-Supported Methods and Individualized Treatment Design in the Case of Geoffrey

This is a response to the commentaries by Dr. Knight (2008) and Dr. Hyer (2008) on “The Case of Geoffrey” (Mohlman et al., 2008). The response focuses on three major themes: the notion of cultural competence in the psychotherapeutic setting; possible risks inherent in and alternatives to the medicalization of mental health treatment for older adults; and the growing use of cognitive remediation in the treatment of psychiatric disorders. We also address some of the other excellent issues raised by Drs. Knight and Hyer regarding cohort effects in the study of older therapy clients and missing elements in the case of Geoffrey.