Predictive role of early treatment dynamics of HBV RNA and HBcrAg for HBeAg seroconversion in children with chronic hepatitis B.

This study aimed to assess the predictive capacity of emerging serological markers, serum HBV RNA and HBcrAg, for HBeAg seroconversion in children with HBeAg-positive chronic hepatitis B (CHB). Treatment-naïve HBeAg-positive CHB children who admitted to the Liver Disease Center of Hunan Children's Hospital between April 2021 and September 2022 and received treatment with the combined entecavir and interferon-alpha treatment were recruited. Serum HBV RNA and HBcrAg were measured at baseline and Weeks 12, 24, and 48 of treatment. Our study showed that serum HBV RNA (HR = 0.71, 95% CI: 0.56-0.91, p = 0.006), HBcrAg (HR = 0.60, 95% CI: 0.43-0.84, p = 0.003), and HBsAg (HR = 0.49, 95%CI: 0.36-0.69, p < 0.001) at Week 12 were independent predictors of HBeAg seroconversion. ROC curve analysis presented that serum HBV RNA decline value (ΔHBV RNA) at Week 36 and HBcrAg decline value (ΔHBcrAg) at Week 12 (AUC = 0.871, p = 0.003 and AUC = 0.810, p = 0.003, respectively) could effectively predict HBeAg seroconversion. Furthermore, the optimal critical values were determined and the children with ΔHBV RNA > 3.759 log10 copies/mL at Week 36 or ΔHBcrAg >0.350 log10 U/mL at Week 12 more likely to achieve HBeAg seroconversion. The serum HBV RNA and HBcrAg provide new insights into the treatment of CHB in children. Early assessment of serum HBV RNA and HBcrAg during treatment can assist clinical decision-making and optimize individualized therapeutic approaches.

Relevance of pharmacogenetics and pharmacogenomics in veterinary clinical practice: A review.

The recent advances in high-throughput next-generation sequencing technologies have heralded the arrival of the Big Data era. As a result, the use of pharmacogenetics in drug discovery and individualized drug therapy has transformed the field of precision medicine. This paradigm shift in drug development programs has effectively reshaped the old drug development practices, which were primarily concerned with the physiological status of patients for drug development. Pharmacogenomics bridges the gap between pharmacodynamics and pharmacokinetics, advancing current diagnostic and treatment strategies and enabling personalized and targeted drug therapy. The primary goals of pharmacogenetic studies are to improve drug efficacy and minimize toxicities, to identify novel drug targets, to estimate drug dosage for personalized medicine, and to incorporate it as a routine diagnostic for disease susceptibility. Although pharmacogenetics has numerous applications in individualized drug therapy and drug development, it is in its infancy in veterinary medicine. The objective of this review is to present an overview of historical landmarks, current developments in various animal species, challenges and future perspectives of genomics in drug development and dosage optimization for individualized medicine in veterinary subjects.

Microbiota, Tryptophan and Aryl Hydrocarbon Receptors as the Target Triad in Parkinson's Disease-A Narrative Review.

In the era of a steadily increasing lifespan, neurodegenerative diseases among the elderly present a significant therapeutic and socio-economic challenge. A properly balanced diet and microbiome diversity have been receiving increasing attention as targets for therapeutic interventions in neurodegeneration. Microbiota may affect cognitive function, neuronal survival and death, and gut dysbiosis was identified in Parkinson's disease (PD). Tryptophan (Trp), an essential amino acid, is degraded by microbiota and hosts numerous compounds with immune- and neuromodulating properties. This broad narrative review presents data supporting the concept that microbiota, the Trp-kynurenine (KYN) pathway and aryl hydrocarbon receptors (AhRs) form a triad involved in PD. A disturbed gut-brain axis allows the bidirectional spread of pro-inflammatory molecules and α-synuclein, which may contribute to the development/progression of the disease. We suggest that the peripheral levels of kynurenines and AhR ligands are strongly linked to the Trp metabolism in the gut and should be studied together with the composition of the microbiota. Such an approach can clearly delineate the sub-populations of PD patients manifesting with a disturbed microbiota-Trp-KYN-brain triad, who would benefit from modifications in the Trp metabolism. Analyses of the microbiome, Trp-KYN pathway metabolites and AhR signaling may shed light on the mechanisms of intestinal distress and identify new targets for the diagnosis and treatment in early-stage PD. Therapeutic interventions based on the combination of a well-defined food regimen, Trp and probiotics seem of potential benefit and require further experimental and clinical research.

Association between 21-gene-assay and detection of disseminated tumor cells in patients with early breast cancer: results from the IRMA trial.

PURPOSE: Disseminated tumor cells (DTCs) in the bone marrow (BM) are known to be of prognostic value for patients with early breast cancer (EBC). In addition to histopathological features, multigene expression assays, such as the commercially available 21-gene Breast Recurrence Score® assay, have been validated for evaluating prognosis and making decisions concerning adjuvant treatment in EBC. In a previous retrospective study from our group, the 21-gene assay was shown to be associated with DTC-detection. A secondary endpoint of the prospective IRMA trial was to evaluate the association between Recurrence Score® (RS) result and tumor cell dissemination in patients with EBC. METHODS: DTC-status and RS result were assessed in patients with ER-positive/HER2-negative EBC with 0-3 pathologic lymph nodes who underwent primary surgical treatment at the Department for Women's Health of Tuebingen University, Germany. RESULTS: Patients with a high RS result (≥ 26) were more frequently DTC-positive (22.6%) than patients with a low RS result (8.6%, p = 0.034). The odds for DTC-positivity increased with rising RS values (p = 0.047). CONCLUSION: We therefore confirm that a high genomic risk is associated with tumor cell dissemination into the BM. Further trials are needed to investigate whether therapeutic decisions could be further individualized by combining DTC-status and prognostic gene signature testing.

Analysis of the Polymorphisms and Expression Levels of the BCL2, BAX and c-MYC Genes in Patients with Ovarian Cancer.

Ovarian cancer (OC) is one of the biggest problems in gynecological oncology and is one of the most lethal cancers in women worldwide. Most patients with OC are diagnosed at an advanced stage; therefore, there is an urgent need to find new biomarkers for this disease. Gene expression profiling is proving to be a very effective tool for exploring new molecular markers for OC patients, although the relationship between such markers and patient survival and clinical outcomes is still elusive. Moreover, polymorphisms in genes encoding both apoptosis-associated proteins and oncoproteins may serve as key markers of cancer susceptibility. The aim of our study was to analyze the polymorphisms and expressions of the BCL2, BAX and c-MYC genes in a group of 198 women, including 98 with OC. The polymorphisms and mRNA expressions of the BCL2, BAX and c-MYC genes were analyzed using real-time PCR. The analysis of the BAX (rs4645878; G>A) and c-MYC (rs4645943; C>T) polymorphisms showed no association with ovarian cancer risk. The BCL2 polymorphism (rs2279115; C>A) showed a significant difference in the frequency of genotypes between the studied groups (CC: 23.47% vs. 16.00%, AA: 25.51% vs. 37.00%; p = 0.046; OR = 1.61). Furthermore, the expression levels of the BCL2 and c-MYC genes showed a decrease at the transcript level for OC patients compared to the control group (BCL2: 17.46% ± 3.26 vs. 100% ± 8.32; p < 0.05; c-MYC: 37.56% ± 8.16 vs. 100% ± 9.12; p < 0.05). No significant changes in the mRNA level were observed for the BAX gene (104.36% ± 9.26 vs. 100% ± 9.44; p > 0.05). A similar relationship was demonstrated in the case of the protein expressions of the studied genes. These findings suggest that the CC genotype and C allele of the BCL2 polymorphism could be genetic risk factors for OC development. A gene expression analysis indicated that BCL2 and c-MYC are associated with OC risk.

Individualized or Uniform De-Escalation Strategies for Antiplatelet Therapy in Acute Coronary Syndrome: A Review of Clinical Trials with Platelet Function Testing and Genetic Testing-Based Protocols.

This comprehensive literature review assessed the effectiveness of precision medicine approaches in individualizing P2Y12 de-escalation strategies, such as platelet function testing guidance, genetic testing guidance, and uniform de-escalation, for acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). Analyzing six trials with a total of 13,729 patients, the cumulative analyses demonstrated a significant reduction in major adverse cardiac events (MACE), net adverse clinical events (NACE), and major and minor bleeding events with P2Y12 de-escalation. Specifically, the analysis found a 24% reduction of MACE and a 22% reduction of adverse event risk (relative risk (RR) 0.76, 95% confidence interval (CI): 0.71-0.82, and RR: 0.78, 95% CI 0.67-0.92, respectively). Reductions in bleeding events were highest with uniform unguided de-escalation, followed by guided de-escalations, while ischemic event rates were similarly lower across all three strategies. Although the review highlights the potential of individualized P2Y12 de-escalation strategies to offer a safer alternative to the long-term potent P2Y12 inhibitor-based dual antiplatelet therapy, it also indicates that laboratory-guided precision medicine approaches may not yet offer the expected benefits, necessitating further research to optimize individualized strategies and evaluate the potential of precision medicine approaches in this context.

An eight centre, retrospective, clinical practice data analysis of algorithm-based treatment with follitropin delta.

RESEARCH QUESTION: Can efficacy and success rates of the first recombinant FSH expressed in a human cell line with an individualized dosing algorithm based on body weight and anti-Müllerian hormone (AMH) as shown in the ESTHER-1 trial be confirmed in routine clinical practice? DESIGN: In eight reproductive medicine centres in Germany, observational data of 360 women who underwent ovarian stimulation with follitropin delta were evaluated as part of the quality control from January 2018 to June 2019. The data were analysed retrospectively. RESULTS: Mean age of patients was 33.5 (±3.8) years. Pretreatment AMH concentrations ranged from <0.5 ng/ml or 3.6 pmol/l (2.5%) to >5.6 ng/ml or 40 pmol/l (19.7%), with 79.7% of all AMH measurements above 2.0 ng/ml or 14.5 pmol/l. The mean number of oocytes obtained in n = 359 first follitropin delta cycles was 11.2 (±6.7) oocytes with 42.1% of patients having between eight and 14 oocytes retrieved at oocyte retrieval. The average clinical pregnancy rate in the first cycle with a fresh embryo transfer was 38.2% with a mean of 1.4 embryos per transfer. The cumulative pregnancy rate was 49.4% for the first stimulation cycle (including cryopreservation cycles generated from the first stimulation cycle). CONCLUSION: The goal of obtaining an adequate number of oocytes (8-14 oocytes) using the follitropin delta dosing algorithm was reached in 42.1% of patients despite a wide range of pretreatment AMH values, while achieving very good clinical pregnancy rates. Hence, algorithm-based ovarian stimulation with follitropin delta remains highly effective in clinical practice.

A single center study that evaluates the preclinical use of a newly developed software and moving bed system to facilitate the spontaneous excretion of residual fragments after primary stone treatment (RIRS or PCNL).

PURPOSE: We developed a Postural Drainage Lithotripsy System (PDLS) that uses the patient's computed tomography urography (CTU) data to reconstruct the three-dimensional figure of the renal pelvis, provides an individualized inversion and overturning angle and uses gravity to remove residual fragments (RFs). The purpose of this study was to investigate PDLS in the treatment of renal RFs. METHODS: A stone with a diameter of 4.0 mm was placed in the upper, middle, and lower calyx of the renal model. A total of 60 trials were applied to 20 renal models. The movement trajectory, passage rate, and postural drainage angle of calculi during the treatment of PDLS were observed. RESULTS: All of the stones in 60 trials were observed to move during treatment, and 53/60 (88%) were relocated successfully to the renal pelvis. The passage rate of the upper calyx was 14/20 (70%), that of the middle calyx was 20/20 (100%), and that of the lower calyx was 19/20 (95%). CONCLUSIONS: PDLS can provide individualized inversion and reversal angles and remove stones from the renal model. More clinical trials are needed to verify the above view and evaluate its efficacy.

BAP1 loss augments sensitivity to BET inhibitors in cancer cells.

The tumor suppressor gene BAP1 encodes a widely expressed deubiquitinase for histone H2A. Both hereditary and acquired mutations are associated with multiple cancer types, including cutaneous melanoma (CM), uveal melanoma (UM), and clear cell renal cell carcinoma (ccRCC). However, there is no personalized therapy for BAP1-mutant cancers. Here, we describe an epigenetic drug library screening to identify small molecules that exert selective cytotoxicity against BAP1 knockout CM cells over their isogenic parental cells. Hit characterization reveals that BAP1 loss renders cells more vulnerable to bromodomain and extraterminal (BET) inhibitor-induced transcriptional alterations, G1/G0 cell cycle arrest and apoptosis. The association of BAP1 loss with sensitivity to BET inhibitors is observed in multiple BAP1-deficient cancer cell lines generated by gene editing or derived from patient tumors as well as immunodeficient xenograft and immunocompetent allograft murine models. We demonstrate that BAP1 deubiquitinase activity reduces sensitivity to BET inhibitors. Concordantly, ectopic expression of RING1A or RING1B (H2AK119 E3 ubiquitin ligases) enhances sensitivity to BET inhibitors. The mechanistic study shows that the BET inhibitor OTX015 exerts a more potent suppressive effect on the transcription of various proliferation-related genes, especially MYC, in BAP1 knockout cells than in their isogenic parental cells, primarily by targeting BRD4. Furthermore, ectopic expression of Myc rescues the BET inhibitor-sensitizing effect induced by BAP1 loss. Our study reveals new approaches to specifically suppress BAP1-deficient cancers, including CM, UM, and ccRCC.

Progress of triazole antifungal agent posaconazole in individualized therapy.

WHAT IS KNOWN AND OBJECTIVE: Posaconazole is the second-generation triazole antifungal agent with widespread clinical application. Posaconazole exposure is influenced by various factors such as drug interactions, disease state and diet, resulting in a high interindividual variability in many patients and failure to ensure therapeutic efficacy. Therefore, it is necessary to conduct individualized therapy on posaconazole to ensure the efficacy and safety of treatment. METHODS: Articles were identified through PubMed using the keywords such as "posaconazole," "therapeutic drug monitoring" and "Population pharmacokinetics" from 1 January 2001 to 30 April 2022. RESULTS AND DISCUSSION: In this paper, we review the individualized treatment studies of posaconazole from the three aspects of therapeutic drug monitoring, population pharmacokinetic study and Monte Carlo simulation to provide reference for in-depth individualized posaconazole dosing studies. WHAT IS NEW AND CONCLUSION: This review suggests that therapeutic drug monitoring should be performed in patients taking posaconazole to adjust the dosage and assess the efficacy and cost-effectiveness of posaconazole under different clinical conditions and different dosing regimens through Monte Carlo simulations. In the future, a more detailed delineation and comprehensive examination of posaconazole PPK for specific populations requires further study.

Leucovorin (folinic acid) rescue for high-dose methotrexate: A review.

High-dose methotrexate (HDMTX) is active against various malignancies; it possesses serious toxicities and is associated with patient characteristics, dosage regimens, comedications, and physiological status. There are many strategies to overcome HDMTX-induced toxicities, such as hydration, alkalization, leucovorin rescue, and haemodialysis. Leucovorin rescue is a cornerstone for toxicity prevention in HDMTX treatment. However, the leucovorin dose adjustment and the existence of leucovorin overrescue are still controversial. At present, various methods for calculating leucovorin doses in different tumour types have been proposed, including empirical calculations based on MTX plasma concentration, the Bleyer nomogram, and other methods. Nonetheless, leucovorin rescue protocols differ greatly across tumour types and medical institutions. Further studies are needed to investigate the optimal dosage regimen for leucovorin rescue in various tumours using HDMTX.

Can we predict unresponsiveness to methotrexate in rheumatoid arthritis? A pharmacogenetic study.

OBJECTIVE: Methotrexate (MTX) is the anchor drug in the treatment of rheumatoid arthritis (RA) and the therapeutic response to MTX has been observed to vary widely among these patients. The aim of this study was to investigate ABCB1 gene (the multidrug resistant 1 gene; MDR1 gene) polymorphism in patients with RA and to evaluate the relation between MTX unresponsiveness and this polymorphism. METHODS: Forty-five patients with RA administered MTX were included in this pharmacogenetic cross-sectional study. The gender, age, body mass index (BMI), rheumatoid factor (RF) positivity, anti-cyclic citrullinated peptide (anti-CCP) positivity, doses of MTX and glucocorticoids were recorded. In addition, initial and third month disease activity (DAS28, Simplified and Clinical Disease Activity Index; SDAI and CDAI) scores were evaluated. We also examined frequencies of two single-nucleotide polymorphisms (SNPs), G2677T and C3435T, within the gene encoding ABCB1. RESULTS: 22 patient's responsive and 20 patients unresponsive to MTX were enrolled. Initial demographic and disease related factors were similar between patients responsive or nonresponsive to MTX. In the third month evaluation, disease activity scores were significantly higher in patients unresponsive to MTX (p < 0.05). In addition, almost all patients unresponsive to MTX (19 of the 20 patients) presented heterozygosity in C3435T (p < 0.000). CONCLUSION: We determined heterozygosity in C3435T SNP of ABCB1 gene (multidrug resistant 1 gene) in almost all patients with RA who were non-responders to MTX. This result may contribute to predict unresponsiveness to MTX in RA. Individualized treatment strategies based on the pharmacogenetic characteristics of MTX may lead to optimization of the treatment.

Harnessing Tumor Mutations for Truly Individualized Cancer Vaccines.

T cells are key effectors of anticancer immunity. They are capable of distinguishing tumor cells from normal ones by recognizing major histocompatibility complex-bound cancer-specific peptides. Accumulating evidence suggests that peptides associated with T cell-mediated tumor rejection arise predominantly from somatically mutated proteins and are unique to every patient's tumor. Knowledge of an individual's cancer mutanome (the entirety of cancer mutations) allows harnessing this enormous tumor cell-specific repertoire of highly immunogenic antigens for individualized cancer vaccines. This review outlines the preclinical and clinical state of individualized cancer vaccine development and the challenges ahead.

Impact of individualized management of breakthrough cancer pain on quality of life in advanced cancer patients: CAVIDIOPAL study.

PURPOSE: The main aim of the study was to assess the impact of individualized management of breakthrough cancer pain (BTcP) on quality of life (QoL) of patients with advanced cancer in clinical practice. METHODS: A prospective, observational, multicenter study was conducted in patients with advanced cancer that were assisted by palliative care units. QoL was assessed with the EORTC QLQ-C30 questionnaire at baseline (V0) and after 28 days (V28) of individualized BTcP therapy. Data on background pain, BTcP, comorbidities, and frailty were also recorded. RESULTS: Ninety-three patients completed the study. Intensity, duration, and number of BTcP episodes were reduced (p < 0.001) at V28 with individualized therapy. Transmucosal fentanyl was used in 93.8% of patients, mainly by sublingual route. Fentanyl titration was initiated at low doses (78.3% of patients received doses of 67 µg, 100 µg, or 133 µg) according to physician evaluation. At V28, mean perception of global health status had increased from 31.1 to 53.1 (p < 0.001). All scales of EORTC QLQ-C30 significantly improved (p < 0.001) except physical functioning, diarrhea, and financial difficulties. Pain scale improved from 73.6 ± 22.6 to 35.7 ± 22.3 (p < 0.001). Moreover, 85.9% of patients reported pain improvement. Probability of no ≥ 25% improvement in QoL was significantly higher in patients ≥ 65 years old (OR 1.39; 95% CI 1.001-1.079) and patients hospitalized at baseline (OR 4.126; 95% CI 1.227-13.873). CONCLUSION: Individualized BTcP therapy improved QoL of patients with advanced cancer. Transmucosal fentanyl at low doses was the most used drug. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov database (NCT02840500) on July 19, 2016.

A UPLC-MS/MS method for simultaneous determination of nine antiepileptic drugs in human plasma and its application in TDM.

With the purpose of carrying out therapeutic drug monitoring (TDM) of nine antiepileptic drugs simultaneously in the clinic, a UPLC-MS/MS assay method was developed and validated. Separation of antiepileptic drugs and internal standard (naproxen and diazepam) was performed on an Agilent Eclipse XDB-C18 column (50.0 × 2.1 mm, 1.7 µm) using water and acetonitrile as mobile phase for gradient elution. Polarity switch ionization mode (positive-negative-positive) was performed in a total run time of 3.0 min. The method validation was conducted based on bioanalytical method validation guidance, including specificity, calibration curve, precision, accuracy, recovery, matrix effect, stability and dilution integrity, and all of the results satisfied the requirements. Consequently, the proposed method was applied to the TDM of nine antiepileptic drugs and was proved to be sensitive, reliable and specific to determine antiepileptic drugs in human plasma simultaneously. Meanwhile, the TDM results showed that the plasma drug concentration of many patients was not within the effective therapeutic range, especially those taking topiramate, oxcarbazepine and levetiracetam, which was of great guiding significance to rational drug use and timely adjustment of the treatment plan. Therefore, individualized therapy based on advanced analytical methods and TDM theory is of great practical significance.

[Reducing tinnitus intensity : Pilot study to attenuate tonal tinnitus using individually spectrally optimized near-threshold noise]. / Reduktion der Tinnituslautstärke : Pilotstudie zur Abschwächung von tonalem Tinnitus mit schwellennahem, individuell spektral optimiertem Rauschen.

BACKGROUND: Around 15% of the general population is affected by tinnitus, but no real cure exists despite intensive research. Based on our recent causal model for tinnitus development, we here test a new treatment aimed at counteracting the perception. This treatment is based on the stochastic resonance phenomenon at specific auditory system synapses that is induced by externally presented near-threshold noise. OBJECTIVE: This pilot study will investigate whether individually spectrally adapted noise can successfully reduce chronic tonal/narrow-band tinnitus during stimulation. MATERIALS AND METHODS: Hearing loss (HL) as well as tinnitus pitch (TP) and loudness (TL) were audiometrically measured in 22 adults (46.6±16.3 years; 4 women) with tinnitus. Based on these measurements, up to eight different noise stimuli with five intensities (-20 to +20 dB SL) were generated. These were presented for 40 s each via audiologic headphones in a soundproof chamber. After each presentation, the change in TL was rated on a five-level scale (-2 to +2). RESULTS: We found patients (n = 6) without any improvement in their TL perception as well as patients with improvement (n = 16), where stimulation around the TP was most effective. The groups differed in post-hoc analysis of their audiograms: the effectiveness of our new therapeutic strategy obviously depends on the individual HL, and was most effective in normal-hearing tinnitus patients and those with mild HL. CONCLUSION: Subjective TL could be reduced in 16 out of 22 patients during stimulation. For a possible success of a future therapy, the HL seems to be of relevance.

[Circulating tumor cells in the diagnosis and treatment of early and advanced prostate cancer].

Circulating tumor cells (CTC) are tumor cells that escape from the primary or metastatic tumor into the circulatory system, and closely related to cancer metastasis. Since the samples can be obtained through simple and minimally invasive blood sampling operations, CTCs have a great clinical potential. PCa is one of the most common malignant tumors in men. In recent years, many scholars have conducted studies as to whether CTC technology can be used for the diagnosis and treatment of PCa, as well as for more accurate prediction of the risk of progression. This article summarizes the advances in researches relating CTC technology and the diagnosis and treatment of PCa. CTC detection has been developed from simple counting to phenotypic classification, and even to its combination with the determination of the expressions of specific genes (such as AR, AR-V7, etc.) and single-cell sequencing. Some reports showed that CTC technology has a certain significance in the early diagnosis of PCa, but its main value is demonstrated in drug sensitivity and prognosis evaluation in the late stage of the malignancy. The standardized detection methods and reference values of CTCs in PCa will be important research orientations in the near future.

Breast cancer organoids from a patient with giant papillary carcinoma as a high-fidelity model.

BACKGROUND: Papillary carcinoma is an uncommon type of breast cancer. Additionally, patients with huge breast papillary carcinoma are extremely rare in clinical practice. To improve therapeutic effect on such patients, it is urgent to explore biologically and clinically relevant models of the disease to discover effective drugs. METHODS: We collected surgical tumor specimens from a 63-year-old Chinese woman who has been diagnosed breast papillary carcinoma. The tumor was more than 15 cm in diameter, and applied to establish patient-derived papillary carcinoma organoids that could continuously propagate for more than 6 months. RESULTS: The papillary carcinoma organoids matched the histological characteristics of orginal tumor by H&E staining identification, and maintained the expression of the breast cancer biomarkers by IHC, including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER2) and antigen Ki-67 (Ki67). In addition, we performed a 3-D drug screening to examine the effects of endocrine drugs (Fulvestrant, Tamoxifen) and targeted therapy drugs (Palbociclib, Everolimus, BKM120) on breast papillary carcinoma in the mimic in vivo environment. The drug sensitivities of our breast papillary carcinoma organoids were investigated as follows, Fulvestrant (IC50 0.275 µmol), Palbociclib (IC50 2.21 µmol), BKM120 (IC50 3.81 µmol), Everolimus (IC50 4.45 µmol), Tamoxifen (IC50 19.13 µmol). CONCLUSIONS: These results showed that an effective organoid platform for 3-D in vitro culture of breast cancer organoids from patients with breast papillary carcinoma could be used to identify possible treatments, and might be commonly applied to explore clinicopathological characteristics of breast papillary carcinoma.

A novel epigenetic signature for overall survival prediction in patients with breast cancer.

BACKGROUND: Breast cancer is the most common malignancy in female patients worldwide. Because of its heterogeneity in terms of prognosis and therapeutic response, biomarkers with the potential to predict survival or assist in making treatment decisions in breast cancer patients are essential for an individualised therapy. Epigenetic alterations in the genome of the cancer cells, such as changes in DNA methylation pattern, could be a novel marker with an important role in the initiation and progression of breast cancer. METHOD: DNA methylation and RNA-seq datasets from The Cancer Genome Atlas (TCGA) were analysed using the Least Absolute Shrinkage and Selection Operator (LASSO) Cox model. Applying gene ontology (GO) and single sample gene set enrichment analysis (ssGSEA) an epigenetic signature associated with the survival of breast cancer patients was constructed that yields the best discrimination between tumour and normal breast tissue. A predictive nomogram was built for the optimal strategy to distinguish between high- and low-risk cases. RESULTS: The combination of mRNA-expression and of DNA methylation datasets yielded a 13-gene epigenetic signature that identified subset of breast cancer patients with low overall survival. This high-risk group of tumor cases was marked by upregulation of known cancer-related pathways (e.g. mTOR signalling). Subgroup analysis indicated that this epigenetic signature could distinguish high and low-risk patients also in different molecular or histological tumour subtypes (by Her2-, EGFR- or ER expression or different tumour grades). Using Gene Expression Omnibus (GEO) the 13-gene signature was confirmed in four external breast cancer cohorts. CONCLUSION: An epigenetic signature was discovered that effectively stratifies breast cancer patients into low and high-risk groups. Since its efficiency appears independent of other known classifiers (such as staging, histology, metastasis status, receptor status), it has a high potential to further improve likely individualised therapy in breast cancer.

Temozolomide regresses a doxorubicin-resistant undifferentiated spindle-cell sarcoma patient-derived orthotopic xenograft (PDOX): precision-oncology nude-mouse model matching the patient with effective therapy.

Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant cancer, resistant to conventional chemotherapy. A patient with high-grade USCS from a striated muscle was implanted orthotopically in the right biceps femoris muscle of mice to establish a patient-derived orthotopic xenograft (PDOX) model. The PDOX models were randomized into the following groups when tumor volume reached 100 mm3 : G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks); G3, temozolomide (TEM) (25 mg/kg, p.o., daily, for 14 days). Tumor size and body weight were measured with calipers and a digital balance twice a week. TEM significantly inhibited tumor volume growth compared to the untreated control and the DOX-treated group on day 14 after treatment initiation: control (G1): 343 ± 78 mm3 ; DOX (G2): 308 ± 31 mm3 , P = 0.272; TEM (G3): 85 ± 21 mm3 , P < 0.0001. TEM significantly regressed the tumor volume compared to day 0 (P = 0.019). There were no animal deaths in any group. The body weight of treated mice was not significantly different in any group. Tumors treated with DOX were comprised of spindle-shaped viable cells without apparent necrosis or inflammatory changes. In contrast, tumors treated with TEM showed extensive tumor necrosis. The present study demonstrates the potential power of matching the patient with an effective drug and saving the patient needless toxicity from ineffective drugs.