Optimal Clinical Strategy Research Articles

An unusual occurrence: Treacher Collin syndrome with nasal dermoid cyst

Treacher-Collins syndrome (TCS), characterized by autosomal dominant inheritance, affects craniofacial development and presents with diverse clinical manifestations, including facial bone hypoplasia, ear malformations, and ocular abnormalities. The syndrome's association with nasal dermoid cysts is rare and poorly documented in the literature. We present a case report of a 10-year-old male with TCS who presented with a nasal dermoid cyst, a noteworthy and atypical finding within this patient population. The patient exhibited typical features of TCS, including facial asymmetry, malar and mandibular hypoplasia, and microtia. The diagnosis was confirmed through clinical evaluation and diagnostic imaging, which revealed additional anomalies such as conductive hearing loss and absence of the external auditory canal. Surgical excision of the nasal dermoid cyst was performed, utilizing the V-Y advancement glabellar flap technique for closure. This case underscores the importance of comprehensive multidisciplinary care in managing complex conditions like TCS, where treatment strategies must address both medical needs and cosmetic outcomes. Further exploration of rare associations like nasal dermoid cysts in TCS contributes to a broader understanding of the syndrome's phenotypic variability and informs optimal clinical management strategies.

ETMR-32. SUPRATENTORIAL NEUROEPITHELIAL TUMOR WITH PLAGL1 FUSION: A CASE REPORT

Abstract BACKGROUND Supratentorial neuroepithelial tumor with PLAGL1 fusion has emerged as a novel subgroup within pediatric brain tumors. Despite its recent identification, critical aspects such as optimal clinical characteristics and management strategies remain elusive. This case report aims to contribute essential insights to the growing body of literature surrounding this enigmatic tumor entity, providing a detailed exploration of its clinical presentation and histopathological features. METHODS A retrospective chart review was conducted, and relevant data were analyzed. RESULTS An 11-year-old female presented with a two-week history of headaches, vomiting, lethargy, and decreased oral intake. Neuroimaging revealed a left frontal lesion with conspicuous mass effect and midline shift, prompting urgent craniotomy due to sudden onset altered mental status. Histopathological analysis revealed a hypercellular glial neoplasm characterized by perivascular pseudorosettes, scattered microcalcifications, microcysts, and areas of necrosis. Immunohistochemical staining revealed GFAP positivity in a substantial subset of tumor cells, rare dot-like positivity for EMA, and diffuse membranous and focal dot-like positivity for D240. Olig2 was mostly negative, indicating the absence of Oligodendrocyte lineage differentiation. The tumor exhibited an elevated Ki-67 proliferation index (approximately 20-30%). Fluorescence in situ hybridization (FISH) studies were negative for RELA, YAP1, and C19MC rearrangements. Targeted next-generation sequencing unveiled an EWSR1-PLAG1 fusion and methylation profiling classified the tumor as “Neuroepithelial tumors, PLAG1-fused” with high confidence. Given the morphological resemblance to anaplastic ependymoma, the therapeutic recommendation included focal irradiation (54 Gy) with proton therapy. The patient, now 12 months post-therapy, is showing favorable clinical outcomes. CONCLUSION This case report underscores the clinical and histopathological intricacies of supratentorial neuroepithelial tumors with PLAGL1 fusion. The identification of EWSR1-PLAG1 fusion and associated molecular alterations informs diagnostic considerations and treatment strategies for this novel entity, emphasizing the importance of continued research to enhance our understanding of its clinical behavior and optimal management approaches.

Diagnostic approach of tuberculous lymphadenitis in a multicenter study.

Tuberculous lymphadenitis (TBLN) is the most common infectious etiology of peripheral lymphadenopathy in adults, in Turkiye. This study aimed to identify the demographic, clinical, and laboratory variables that differentiate TBLN from non-tuberculous lymphadenitis (NTBLN), as well as the etiology of lymphadenopathy in adults. Patients who were over 18 years old and were referred to the infectious disease outpatient clinics with complaints of swollen peripheral lymph nodes, and who underwent lymph node biopsy between 1 January 2010 and 1 March 2021, were included in this multicenter, nested case-control study. A total of 812 patients at 17 tertiary teaching and research hospitals in Turkiye were included in the study. TBLN was the most frequent diagnosis (53.69%). The proportion of patients diagnosed with TBLN was higher among females; and among those who had a higher erythrocyte sedimentation rate, positive purified protein derivative test, and positive interferon-gamma release test result (p < 0.05). However, TBLN was less frequent among patients with generalized lymphadenopathy, bilateral lymphadenopathy, axillary lymphadenopathy, inguinal lymphadenopathy, hepatomegaly, splenomegaly, leukocytosis, and moderately increased C reactive protein levels (p < 0.05). Identifying the variables that predict TBLN or discriminate TBLN from NTBLN will help clinicians establish optimal clinical strategies for the diagnosis of adult lymphadenopathy.

Treatment Strategy for Breast Benign Intraductal Papilloma: A Meta-Analysis.

Currently, the optimal treatment approach for breast benign intraductal papilloma (IDP) diagnosed via biopsy remains uncertain. There is ongoing debate regarding the feasibility of clinical follow-up and the criteria for selective surgical excision. This study aims to conduct a meta-analysis to determine the rate of upgrade from breast benign IDP and identify predictive factors associated with the conversion of benign IDP to high-risk lesions or carcinoma, which could guide healthcare practitioners in selecting the appropriate clinical treatment strategy. We conducted a comprehensive search across multiple databases (PubMed, Web Of Science, Cochrane Library, and Embase) for studies published between 2012 and 2023 that evaluated upgrade rates and predictive factors of breast benign IDP diagnosed via biopsy. In addition, we included studies that reported on the clinical follow-up of patients with breast benign IDP. In total, 32 studies comprising 7371 cases of biopsy-diagnosed breast benign IDP were included. Among these cases, 720 demonstrated an upgrade to high-risk lesions or carcinoma, resulting in an upgrade rate of 6.94% [95% confidence interval (CI): 3.0-8.0%]. A subgroup of 1713 patients was clinically followed up, demonstrating an average follow-up duration of 30.95 months. Among them, 26 cases experienced an upgrade to high-risk lesions or carcinoma, yielding an upgrade rate of 1.51% (95% CI 0.00-2.00). Furthermore, we identified nine predictive factors associated with the upgrading of breast benign IDP, which included age at diagnosis, personal history of breast cancer, family history of breast cancer, multiple IDPs, lesion size ≥ 10 mm, palpable mass, calcification, and the presence of mass and asymmetry in mammographic findings. Although the conversion rate of breast benign IDP to high-risk lesions or carcinoma is relatively low, timely identification of predictive factors associated with benign IDP upgrades may help selecting the optimal clinical treatment strategy, such as surgery for patients with benign IDP presenting one or more predictive factors, while clinical follow-up for those without specific risk factors.

A how-to guide for a precision medicine approach to the diagnosis and treatment of Alzheimer's disease.

The clinical approach to Alzheimer's disease (AD) is challenging, particularly in high-functioning individuals. Accurate diagnosis is crucial, especially given the significant side effects, including brain hemorrhage, of newer monoclonal antibodies approved for treating earlier stages of Alzheimer's. Although early treatment is more effective, early diagnosis is also more difficult. Several clinical mimickers of AD exist either separately, or in conjunction with AD pathology, adding to the diagnostic complexity. To illustrate the clinical decision-making process, this study includes de-identified cases and reviews of the underlying etiology and pathology of Alzheimer's and available therapies to exemplify diagnostic and treatment subtleties. The clinical presentation of Alzheimer's is complex and varied. Multiple other primary brain pathologies present with clinical phenotypes that can be difficult to distinguish from AD. Furthermore, Alzheimer's rarely exists in isolation, as almost all patients also show evidence of other primary brain pathologies, including Lewy body disease and argyrophilic grain disease. The phenotype and progression of AD can vary based on the brain regions affected by pathology, the coexistence and severity of other brain pathologies, the presence and severity of systemic comorbidities such as cardiac disease, the common co-occurrence with psychiatric diagnoses, and genetic risk factors. Additionally, symptoms and progression are influenced by an individual's brain reserve and cognitive reserve, as well as the timing of the diagnosis, which depends on the demographics of both the patient and the diagnosing physician, as well as the availability of biomarkers. The optimal clinical and biomarker strategy for accurately diagnosing AD, common neuropathologic co-morbidities and mimickers, and available medication and non-medication-based treatments are discussed. Real-life examples of cognitive loss illustrate the diagnostic and treatment decision-making process as well as illustrative treatment responses. AD is best considered a syndromic disorder, influenced by a multitude of patient and environmental characteristics. Additionally, AD existing alone is a unicorn, as there are nearly always coexisting other brain pathologies. Accurate diagnosis with biomarkers is essential. Treatment response is affected by the variables involved, and the effective treatment of Alzheimer's disease, as well as its prevention, requires an individualized, precision medicine strategy.

Neoadjuvant SBRT combined with immunotherapy in NSCLC: from mechanisms to therapy.

The utilisation of neoadjuvant immunotherapy has demonstrated promising preliminary clinical outcomes for early-stage resectable non-small-cell lung cancer (NSCLC). Nevertheless, it is imperative to develop novel neoadjuvant combination therapy regimens incorporating immunotherapy to further enhance the proportion of patients who derive benefit. Recent studies have revealed that stereotactic body radiotherapy (SBRT) not only induces direct tumour cell death but also stimulates local and systemic antitumour immune responses. Numerous clinical trials have incorporated SBRT into immunotherapy for advanced NSCLC, revealing that this combination therapy effectively inhibits local tumour growth while simultaneously activating systemic antitumour immune responses. Consequently, the integration of SBRT with neoadjuvant immunotherapy has emerged as a promising strategy for treating resectable NSCLC, as it can enhance the systemic immune response to eradicate micrometastases and recurrent foci post-resection. This review aims to elucidate the potential mechanism of combination of SBRT and immunotherapy followed by surgery and identify optimal clinical treatment strategies. Initially, we delineate the interplay between SBRT and the local tumour immune microenvironment, as well as the systemic antitumour immune response. We subsequently introduce the preclinical foundation and preliminary clinical trials of neoadjuvant SBRT combined with immunotherapy for treating resectable NSCLC. Finally, we discussed the optimal dosage, schedule, and biomarkers for neoadjuvant combination therapy in its clinical application. In conclusion, the elucidation of potential mechanism of neoadjuvant SBRT combined immunotherapy not only offers a theoretical basis for ongoing clinical trials but also contributes to determining the most efficacious therapy scheme for future clinical application.

Renal Dysfunction After Heart Transplant

Moderate or severe renal dysfunction (MSRD) is a frequent complication after heart transplantation. Strategies to delay progression and improve outcomes, such as renoprotective medications and timely referral to nephrology, remain important in providing care to heart transplant recipients with MSRD. What are chronic renal dysfunction's prevalence, risk factors, and optimal clinical management strategies in heart transplant recipients? This single-center, cross-sectional study examined patients who received a heart transplant from January 1, 2000, to June 30, 2011, and followed until December 31, 2011. Moderate or severe renal dysfunction was defined as a glomerular filtration rate of <60 mL/min/1.73 m2. The prevalence of MSRD among 195 heart transplant recipients was 60%. Variables associated with MSRD were female sex (odds ratio [OR]: 4.82; 95% CI, 1.72-13.54), greater age (OR: 1.10 per year; 95% CI, 1.06-1.14), time since transplant (OR: 1.0004 per year; 95% CI, 1.0001-1.0007), and mTOR inhibitor use (OR: 2.89; 95% CI, 1.24-6.71). Tacrolimus use (OR: 0.19; 95% CI, 0.05-0.71) and cyclosporine use (OR: 0.21; 95% CI, 0.05-0.80) were associated with patients without MSRD. Among patients with MSRD, 19.6% were referred to a nephrologist. Median eGFR remained stable at approximately 60 mL/min/1.73 m2 for 3 years after the study. Our results suggest that female sex, older age at transplant, and time since transplant are associated with MSRD in heart transplant recipients. Tacrolimus and cyclosporine use seemed renoprotective, but lower usage and increased mTOR inhibitor use may more likely indicate existing treatment patterns for patients with MSRD.

Rethinking our approach to cancer metabolism to deliver patient benefit.

Altered cellular metabolism is a major mechanism by which tumours support nutrient consumption associated with increased cellular proliferation. Selective dependency on specific metabolic pathways provides a therapeutic vulnerability that can be targeted in cancer therapy. Anti-metabolites have been used clinically since the 1940s and several agents targeting nucleotide metabolism are now well established as standard of care treatment in a range of indications. However, despite great progress in our understanding of the metabolic requirements of cancer and non-cancer cells within the tumour microenvironment, there has been limited clinical success for novel agents targeting pathways outside of nucleotide metabolism. We believe that there is significant therapeutic potential in targeting metabolic processes within cancer that is yet to be fully realised. However, current approaches to identify novel targets, test novel therapies and select patient populations most likely to benefit are sub-optimal. We highlight recent advances in technologies and understanding that will support the identification and validation of novel targets, re-evaluation of existing targets and design of optimal clinical positioning strategies to deliver patient benefit.

New insights into the pathogenesis of necrotizing enterocolitis and the dawn of potential therapeutics

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disorder in premature infants that causes significant morbidity and mortality. Research efforts into the pathogenesis of NEC have discovered a pivotal role for the gram-negative bacterial receptor, Toll-like receptor 4 (TLR4), in its development. TLR4 is activated by dysbiotic microbes within the intestinal lumen, which leads to an exaggerated inflammatory response within the developing intestine, resulting in mucosal injury. More recently, studies have identified that the impaired intestinal motility that occurs early in NEC has a causative role in disease development, as strategies to enhance intestinal motility can reverse NEC in preclinical models. There has also been broad appreciation that NEC also contributes to significant neuroinflammation, which we have linked to the effects of gut-derived pro-inflammatory molecules and immune cells which activate microglia in the developing brain, resulting in white matter injury. These findings suggest that the management of the intestinal inflammation may secondarily be neuroprotective. Importantly, despite the significant burden of NEC on premature infants, these and other studies have provided a strong rationale for the development of small molecules with the capability of reducing NEC severity in pre-clinical models, thus guiding the development of specific anti-NEC therapies. This review summarizes the roles of TLR4 signaling in the premature gut in the pathogenesis of NEC, and provides insights into optimal clinical management strategies based upon findings from laboratory studies.

The effects of correction of vitamin D deficiency in children undergoing hematopoietic stem cell transplantation

Literature data suggest that vitamin D (VD) deficiency may adversely affect many systems of the body, not only skeletal system, as believed earlier, but also central nervous system, cardiovascular system, urinary system, and immune system, which is particularly important for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Two consecutive studies of VD deficiency after allogeneic HSCT in pediatric patients showed that VD deficiency was associated with decreased overall survival. The correction of VD deficiency was also reported to be a challenge, and in some cases higher doses of VD were needed (200 IU/kg/day or more), but even with this more aggressive approach VD deficiency could persist. In this article, we present a literature review on this topic as well as our data on the management of VD deficiency and monitoring of serum 25-hydroxycholecalciferol (25-HVD) levels in 18 children undergoing allogeneic HSCT at our hospital. This study was approved by the Independent Ethics Committee of the Regional Children's Clinical Hospital (Yekaterinburg). Unfortunately, because of the small size of the patient group we were not able to obtain reliable scientific data. However, here we present our approach to the clinical management of VD deficiency, personalized dosing of VD, and safe therapeutic ranges of VD metabolites in blood. The majority of HSCT recipients in our study achieved therapeutic levels of 25-hydroxycholecalciferol. Treatment of VD deficiency in children undergoing allogeneic HSCT is a promising way to improve overall survival, but further studies are needed to develop optimal clinical strategies.

Advances in Molecular Imaging in Infective Endocarditis.

Infective endocarditis (IE) is a growing epidemiological challenge. Appropriate diagnosis remains difficult due to heterogenous etiopathogenesis and clinical presentation. The disease may be followed by increased mortality and numerous diverse complications. Developing molecular imaging modalities may provide additional insights into ongoing infection and support an accurate diagnosis. We present the current evidence for the diagnostic performance and indications for utilization in current guidelines of the hybrid modalities: single photon emission tomography with technetium99m-hexamethylpropyleneamine oxime-labeled autologous leukocytes (99mTc-HMPAO-SPECT/CT) along with positron emission tomography with fluorodeoxyglucose (18F-FDG PET/CT). The role of molecular imaging in IE diagnostic work-up has been constantly growing due to technical improvements and the increasing evidence supporting its added diagnostic and prognostic value. The various underlying molecular processes of 99mTc-HMPAO-SPECT/CT as well as 18F-FDG PET/CT translate to different imaging properties, which should be considered in clinical practice. Both techniques provide additional diagnostic value in the assessment of patients at risk of IE. Nuclear imaging should be considered in the IE diagnostic algorithm, not only for the insights gained into ongoing infection at a molecular level, but also for the determination of the optimal clinical therapeutic strategies.

Multimodal single-cell analyses of peripheral blood mononuclear cells of COVID-19 patients in Japan

SARS-CoV-2 continues to spread worldwide. Patients with COVID-19 show distinct clinical symptoms. Although many studies have reported various causes for the diversity of symptoms, the underlying mechanisms are not fully understood. Peripheral blood mononuclear cells from COVID-19 patients were collected longitudinally, and single-cell transcriptome and T cell receptor repertoire analysis was performed. Comparison of molecular features and patients’ clinical information revealed that the proportions of cells present, and gene expression profiles differed significantly between mild and severe cases; although even among severe cases, substantial differences were observed among the patients. In one severely-infected elderly patient, an effective antibody response seemed to have failed, which may have caused prolonged viral clearance. Naïve T cell depletion, low T cell receptor repertoire diversity, and aberrant hyperactivation of most immune cell subsets were observed during the acute phase in this patient. Through this study, we provided a better understanding of the diversity of immune landscapes and responses. The information obtained from this study can help medical professionals develop personalized optimal clinical treatment strategies for COVID-19.

Medication-related osteonecrosis of the jaw: A literature review and update.

Since the initial description of medication-related osteonecrosis of the jaw (MRONJ) almost two decades ago, the potential pathophysiology and risk factors have been elaborated on in many investigations and guidelines. However, the definitive pathophysiology based on scientific evidence remains lacking. Consequently, the optimal clinical treatment and prevention strategies for MRONJ have not been established. Despite their different mechanisms of action, many drugs, including bisphosphonates, denosumab, angiogenesis inhibitors, and other medications, have been reported to be associated with MRONJ lesions in cancer and osteoporosis patients. Importantly, MRONJ occurs predominantly in the jawbones and other craniofacial regions, but not in the appendicular skeleton. In this up-to-date review, the currently available information and theories regarding MRONJ are presented from both clinical and basic science perspectives. The definition and epidemiology of MRONJ, triggering medication, and histopathology are comprehensively summarized. The immunopathology and the potential pathophysiology based on immune cells such as neutrophils, T and B cells, macrophages, dendritic cells, and natural killer cells are also discussed. In addition, antiangiogenesis, soft tissue toxicity, necrotic bone, osteocyte death, and single-nucleotide polymorphisms are examined. Moreover, other possible mechanisms of MRONJ development are considered based on the unique embryological characteristics, different cell behaviors between jawbones and appendicular skeleton, unique anatomical structures, and sustained bacterial exposure in the oral cavity as a basis for MRONJ site specificity. Based on the literature review, it was concluded that multiple factors may contribute to the development of MRONJ, although which one is the key player triggering MRONJ in the craniofacial region remains unknown.

PLACENTAL MOSAICISM: COMPLETE DISCORDANCE BETWEEN THE PLACENTA AND THE FETUS. CLINICAL CASE RECORD

NIPT with the analysis of all chromosomes for aneuploidy screening. Chromosomal microarray 750K, routine karyotyping and Whole-exome sequencing and Sanger sequencing were used for the analysis of the clinical situation Sonographic fetal abnormalities were accompanied by the placental mosaicism (trisomy 16), fetal partial uniparental disomy of the short arm of chromosome 16. NIPT with the analysis of all chromosomes is a powerful tool to identify placental mosaicism, which in turn can manifest itself as nonspecific abnormalities in biochemical markers, placental dysfunction, growth retardation, fetal malformations, preterm birth, etc. If placental mosaicism is suspected, the optimal clinical strategy is to perform amniocentesis and placentocentesis simultaneously with a complete genetic examination of the obtained material

Differentiation between non-small cell lung cancer and radiation pneumonitis after carbon-ion radiotherapy by 18F-FDG PET/CT texture analysis

The differentiation of non-small cell lung cancer (NSCLC) and radiation pneumonitis (RP) is critically essential for selecting optimal clinical therapeutic strategies to manage post carbon-ion radiotherapy (CIRT) in patients with NSCLC. The aim of this study was to assess the ability of 18F-FDG PET/CT metabolic parameters and its textural image features to differentiate NSCLC from RP after CIRT to develop a differential diagnosis of malignancy and benign lesion. We retrospectively analyzed 18F-FDG PET/CT image data from 32 patients with histopathologically proven NSCLC who were scheduled to undergo CIRT and 31 patients diagnosed with RP after CIRT. The SUV parameters, metabolic tumor volume (MTV), total lesion glycolysis (TLG) as well as fifty-six texture parameters derived from seven matrices were determined using PETSTAT image-analysis software. Data were statistically compared between NSCLC and RP using Wilcoxon rank-sum tests. Diagnostic accuracy was assessed using receiver operating characteristics (ROC) curves. Several texture parameters significantly differed between NSCLC and RP (p < 0.05). The parameters that were high in areas under the ROC curves (AUC) were as follows: SUVmax, 0.64; GLRLM run percentage, 0.83 and NGTDM coarseness, 0.82. Diagnostic accuracy was improved using GLRLM run percentage or NGTDM coarseness compared with SUVmax (p < 0.01). The texture parameters of 18F-FDG uptake yielded excellent outcomes for differentiating NSCLC from radiation pneumonitis after CIRT, which outperformed SUV-based evaluation. In particular, GLRLM run percentage and NGTDM coarseness of 18F-FDG PET/CT images would be appropriate parameters that can offer high diagnostic accuracy.

Langerhans cell histiocytosis: Version 2021.

Children with Langerhnans cell histiocytosis (LCH) develop granulomatous lesions with characteristic clonal CD207+ dendritic cells that can arise as single lesions or life-threatening disseminated disease. Despite the wide range of clinical presentations, LCH lesions are histologically indistinguishable based on severity of disease, and uncertain classification as an immune versus neoplastic disorder has historically challenged the development of optimal clinical strategies for patients with LCH. Recently, activating somatic mutations in MAPK pathway genes, most notably BRAFV600E, have been discovered in almost all cases of LCH. Further, the stage of myeloid differentiation in which the mutation arises defines the extent of disease and risk of developing LCH-associated neurodegeneration. MAPK activation in LCH precursor cells drives myeloid differentiation, inhibits migration, and inhibits apoptosis, resulting in accumulation of resilient pathologic dendritic cells that recruit and activate T cells. Recurrent somatic mutations in MAPK pathway genes have also been identified in related histiocytic disorders: juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease. New insights into pathogenesis support reclassification of these conditions as a myeloid neoplastic disorders. Continued research will uncover opportunities to identify novel targets and inform personalized therapeutic strategies based on cell of origin, somatic mutation, inherited risk factors, and residual disease.

Nomograms incorporating preoperative RDW level for the prediction of postoperative complications and survival in colorectal liver metastases after resection.

This study aimed to investigate the predictive significance of preoperative red cell volume distribution width (RDW) level for prognosis and to establish nomograms incorporating preoperative blood markers to predict postoperative complications and survival in patients with colorectal liver metastases (CRLM). This retrospective study included 380 enrolled CRLM patients who underwent hepatic resection. Predictors of postoperative complications were explored using binary logistic regression analysis. Covariates associated with overall survival (OS) and progression-free survival (PFS) were evaluated through univariate and multivariate Cox regression analyses. Only variables that reached statistical significance at P<0.1 in the univariate analysis were allowed to enter the multivariate analyses. The independent predictors that retained in the final multivariate model were incorporated into nomograms. The optimal cut-off point of preoperative RDW-CV was 16%, and elevated RDW-CV was significantly associated with better prognosis (mPFS: 5.0 vs. 8.9 months, P=0.007; mOS: 59.0 vs. 42.0 months, P=0.041). The optimal cut-off point of preoperative RDW-SD was 43.9 fl, and elevated RDW-SD was significantly associated with worse prognosis (mPFS: 8.0 vs. 13.0 months, P<0.001; mOS:36.8 vs. 70.2 months, P=0.001). A nomogram predicting postoperative complications was constructed based on preoperative gamma-glutamyl transpeptidase (GGT) ≥34.5 U/L, preoperative RDW-CV ≥14.1%, and intraoperative blood loss ≥200.0 mL, with AUROC of 0.658. The calibration curves and Hosmer-Lemeshow test revealed desirable model calibration (chi-square: 3.99, P=0.91). A nomogram predicting PFS was constructed based on preoperative GGT ≥31.0 U/L, preoperative D-dimer ≥0.251 mg/L, preoperative RDW-CV <16.0%, preoperative RDW-SD ≥43.9 fl, positive lymph node metastasis, bilobar liver distribution, and R0 resection with good discrimination (C-index: 0.676±0.016) and calibration. A nomogram for the prediction of OS was constructed with favorable discrimination (C-index: 0.700±0.021) and calibration. Significant differences in PFS and OS were shown among patients stratified into three different risk groups (P<0.001) based on the nomograms. This study first revealed the relationship between preoperative RDW-SD, RDW-CV, and prognosis in patients with CRLM. It also established nomograms especially considering preoperative blood markers to predict postoperative complications, PFS, and OS, which facilitated physicians to determine the optimal clinical management strategies.

The tumor microenvironment shapes the molecular characteristics of exhausted CD8+ T cells.

The persistent antigen stimulation during chronic infections and cancer results in CD8+ T cell exhaustion. The exhausted T (Tex) cells within the tumor microenvironment (TME) are characterized by increased expression of multiple co-inhibitory receptors simultaneously, progressive loss of effector function, poor proliferation and self-renewal capacity, and dysregulated metabolic activity. Emerging insights into molecular mechanisms underlying T cell exhaustion have proposed potential approaches to improve the efficacy of cancer immunotherapy via restoring the effector function of Tex cells. In this review, we summarize the fundamental characteristics (e.g., inhibitory receptors and transcriptional factors) regarding Tex cell differentiation and discuss in particular how those exhaustion features are acquired and shaped by key factors within the TME. Additionally, we discuss the progress and limitations of current cancer immunotherapeutic strategies targeting Tex cells in clinical setting.

Currently favored sampling practices for tumor sequencing can produce optimal results in the clinical setting

Tumor heterogeneity is a consequence of clonal evolution, resulting in a fractal-like architecture with spatially separated main clones, sub-clones and single-cells. As sequencing an entire tumor is not feasible, we ask the question whether there is an optimal clinical sampling strategy that can handle heterogeneity and hypermutations? Here, we tested the effect of sample size, pooling strategy as well as sequencing depth using whole-exome sequencing of ovarian tumor specimens paired with normal blood samples. Our study has an emphasis on clinical application—hence we compared single biopsy, combined local biopsies and combined multi-regional biopsies. Our results show that sequencing from spatially neighboring regions show similar genetic compositions, with few private mutations. Pooling samples from multiple distinct regions of the primary tumor did not increase the overall number of identified mutations but may increase the robustness of detecting clonal mutations. Hypermutating tumors are a special case, since increasing sample size can easily dilute sub-clonal private mutations below detection thresholds. In summary, we compared the effects of sampling strategies (single biopsy, multiple local samples, pooled global sample) on mutation detection by next generation sequencing. In view of the limitations of present tools and technologies, only one sequencing run per sample combined with high coverage (100–300 ×) sequencing is affordable and practical, regardless of the number of samples taken from the same patient.

Comprehensive Evaluation of Relapse Risk (CERR) Score for Colorectal Liver Metastases: Development and Validation.

The calculation of the tumor burden score (TBS) is not perfect because the bilobar spread of colorectal liver metastasis (CRLM) is neglected. The identification of an ideal prognostic scoring system for CRLM remains controversial. Patients who underwent curative intent liver resection for CRLM from one medical center were enrolled in cohort 1 (787 patients) and cohort 2 (162 patients). Tumor relapse-free survival (RFS) was the main outcome. A Cox regression model was used to identify independent predictors of prognosis. The time-dependent area under the curve, calibration curve, and C-index were employed to validate the predictive ability of the survival model. Modified TBS (mTBS) was established by a mathematical equation with parameters including CRLM size, CRLM number, and unilobar or bilobar metastasis. Five preoperative predictors of worse RFS were identified in cohort 1 and incorporated into the Comprehensive Evaluation of Relapse Risk (CERR) score: KRAS/NRAS/BRAF-mutated tumor (1 point); node-positive primary (1 point); extrahepatic disease (1 point); carcinoembryonic antigen level > 200 ng/mL or carbohydrate antigen 19-9 (CA19-9) >200 U/mL (1 point); and mTBS between 5 and 11 (1 point) or 12 and over (2 points). Patients in cohort 1 were stratified by their CERR score into risk groups: the high-risk group (CERR score 4 or more), the medium-risk group (CERR score 2-3), and the low-risk group (CERR score 0-1). Importantly, internal validation in cohort 1 and further validation in cohort 2 both showed the superior discriminatory capacity of the CERR score. mTBS should be promoted. The CERR score is a powerful prognostic tool that can help determine optimal clinical management strategies. This work resulted in the successful modification of the tumor burden score and development of a comprehensive and practical prognostic scoring system-the Comprehensive Evaluation of Relapse Risk (CERR) score. The CERR score, with a better prognostic discriminatory ability, outperformed the Fong score. Perhaps more importantly, the CERR score is a powerful prognostic tool because it unified the most consistently reported prognostic factors. Therefore, the CERR score can assist doctors in determining optimal clinical management strategies.