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PubMed1985

[Morphological prognosis factors in ovarian carcinoma].

Ovarian tumours form a broad spectrum of histological types which reflect significant differences with regard to their biological behaviour and their responsiveness to radiological and cytostatical therapy. Precise subclassification is a precondition for selective therapy. A special subclass of tumours is represented by so-called borderline tumours which form a significant proportion of the overall group of epithelian ovarian neoplasms. Borderline tumours are histologically defined tumours which are neither fully benign nor overtly malignant. Though capable to metastasise they are of low malignant potential and favourable prognosis. In clinical statistics borderline tumours should be registered as a special entity. Within the ordinary group of malignant epithelial tumours histological grading has proven to be of prognostic significance. Amongst a great spectrum of useful cyto-histological criteria, nuclear polymorphism. The number of mitoses, and necrosis are the most important predictive factors.

Adenocarcinoma↗
PubMed2024

LRP4 mutations promote tumor progression and resistance to anti-PD-1 therapy in recurrent hepatocellular carcinoma.

BACKGROUND AND AIMS: HCC recurrence is a major factor limiting long-term survival and the cause of most deaths in patients with HCC. However, molecular characterization and potential therapeutic targets of recurrent HCC remain mostly unknown. APPROACH AND RESULTS: We performed whole-exome sequencing in 63 matched primary and recurrent HCC tumors and combined the data with whole-genome sequencing results in 43 paired samples from our previous study. Sanger sequencing was used to identify all low-density lipoprotein receptor-related protein 4 ( LRP4 ) coding exons in 203 additional patients with recurrent HCC. We identified LRP4 somatic mutations in 7.8% (24/309) of recurrent tumors and only 0.97% (3/309) of primary tumors ( p <0.001). Prognosis after the second liver resection was poorer in patients with an LRP4 mutation. Biofunctional investigations demonstrated that inactivating LRP4 mutations promoted tumor progression and immunosuppression. Mechanistically, mutated LRP4 reduced intratumoral conventional type 1 dendritic cell and CD8 + T cell infiltration by repressing C-C motif chemokine ligand 4 expression and secretion through activation of &#x3b2;-catenin signaling, resulting in resistance to anti-programmed cell death protein-1 therapy. Patients with recurrent HCC carrying an LRP4 mutation did not benefit from anti-programmed cell death protein-1 treatment after their second resection surgery. A &#x3b2;-catenin inhibitor-reversed LRP4-induced resistance to anti-programmed cell death protein-1 therapy in humanized tumor-bearing mice. CONCLUSIONS: Our results identified novel LRP4 mutations important in recurrent HCC. Inactivating LRP4 mutations were associated with resistance to anti-programmed cell death protein-1 therapy and could be useful biomarkers for precision therapy in patients with recurrent HCC.

Humans↗
PubMed2006

Update on radiation therapy in prostate cancer.

Higher doses of radiation result in improved clinical control of prostate cancer,and the recent advances in prostate cancer radiotherapy are designed to escalate dose while minimizing toxicity. To achieve this goal, tighter treatment margins are needed, which require more accurate delineation of the prostate target and normal tissue at the time of treatment planning and before actual daily treatments. Modem radiation therapy techniques can deposit conformal dose virtually anywhere in the body; however, this precise therapy is of no value if it is not accurately hitting the target. Whether dose escalation is achieved by external beam techniques (eg, IMRT, protons) or brachytherapy, these ba-sic planning and delivery considerations are essentially the same. Future directions in prostate radiation therapy will use even higher radiation doses,alternative fractionation patterns, intraprostatic targets (eg, prostate tumor seen on MRI), and improved patient selection regarding which patients will benefit the most from these advanced techniques.

Dose-Response Relationship, Radiation↗
PubMed2026

Synergistic HMGN1 and VP64 Fusions Potentiate High-Precision and PAM-Flexible Base Editing.

RNA-guided CRISPR-derived base editors (BEs) have revolutionized genome editing by enabling targeted base substitutions. However, their application is frequently constrained by the stringent requirement for PAM sequences and low editing precision (bystander editing). Here, we present a robust strategy to overcome these limitations by coupling SpRY, a near-PAM-less Cas9 variant, with truncated CDA1 cytidine deaminases. While this combination enables precise editing of virtually any cytosine in the genome, it initially exhibited suboptimal efficiency. To address this, we systematically screened a diverse panel of candidate DNA-binding proteins and identified that the synergistic fusion of HMGN1 and VP64 substantially enhances editing activity without compromising precision. Importantly, this enhanced editing efficiency was achieved without markedly increasing off-target effects. Our new BEs demonstrated robust performance not only in yeast but also in rice, suggesting broad applicability in gene therapy, precision breeding, and fundamental research.

Gene Editing↗
PubMed1994

Approach to the patient with rheumatoid arthritis.

RA remains a therapeutic challenge. Despite substantial data from therapeutic trials, the precise therapy of this often debilitating disease remains controversial. A variety of agents are available to the clinician for the treatment of this disease, yet the precise timing of their use and the determination of situations in which efficacy is most likely to be observed is still unclear. However, it is obvious that earlier intervention and more aggressive forms of therapy are currently advocated by most rheumatologists. Given the rapidity with which this disease can induce substantial morbidity, the use of second-line agents early in the course of this process is warranted. Whether or not combination therapy provides any benefit is still unproved. As our understanding of the pathogenic mechanisms involved in the development of RA evolve, and with the development of newer immunomodulatory agents, it is likely that more specific forms of therapy can be developed. It is hoped that these protocols will permit more precise treatment of the abnormalities leading to this disease without global suppression of the immune system or other unacceptable side effects.

Anti-Inflammatory Agents↗
PubMed1996

Magnetic resonance imaging changes after stereotactic radiation therapy for childhood low grade astrocytoma.

BACKGROUND: Stereotactic radiotherapy (SRT) is fractionated radiotherapy delivered under stereotactic guidance to produce highly focal and precise therapy. We studied the incidence of imaging changes that can mimic tumor progression after completion of SRT for childhood low grade astrocytoma. METHODS: Between June 1992 and September 1994, we prospectively treated 28 children with low grade astrocytomas with SRT. The patients ranged in age from 2 to 22 years (median: 10 yrs) and none had received prior radiation therapy or radiosurgery. Routine fractionation was employed (180-200 centigray[cGy]) to a total dose of 5220-6000 cGy over 5 to 6 weeks. All of the patients underwent initial and follow-up magnetic resonance imaging (MRI) according to protocol. RESULTS: Median clinical follow-up for the 28 patients was 24 months (range, 5-32 mos) with a median radiographic follow-up of 15 months (range, 3-26 mos). Fifteen patients had reduction in tumor size, one patient had stable disease. Twelve patients (43%) developed increased size of the lesion, increased signal intensity or enhancement, cysts or cavitations, and an increase in edema or mass effect on follow-up MRI. Most of these changes occurred between 9 and 12 months after the start of SRT and resolved or decreased by 15 to 21 months. All but one patient had normal or stable neurologic examinations. CONCLUSIONS: Treatment-related MRI changes are common after conventionally fractionated schedules using stereotactic radiation techniques for patients with low grade astrocytomas. These changes can be distinguished from tumor progression by their transient nature as well as the general absence of clinical symptoms.

Adolescent↗
PubMed1993

Cross-calibration of liquid and solid QCT calibration standards: corrections to the UCSF normative data.

Quantitative computed tomography (QCT) has been shown to be a precise and sensitive method for evaluating spinal bone mineral density (BMD) and skeletal response to aging and therapy. Precise and accurate determination of BMD using QCT requires a calibration standard to compensate for and reduce the effects of beam-hardening artifacts and scanner drift. The first standards were based on dipotassium hydrogen phosphate (K2HPO4) solutions. Recently, several manufacturers have developed stable solid calibration standards based on calcium hydroxyapatite (CHA) in water-equivalent plastic. Due to differences in attenuating properties of the liquid and solid standards, the calibrated BMD values obtained with each system do not agree. In order to compare and interpret the results obtained on both systems, cross-calibration measurements were performed in phantoms and patients using the University of California San Francisco (UCSF) liquid standard and the Image Analysis (IA) solid standard on the UCSF GE 9800 CT scanner. From the phantom measurements, a highly linear relationship was found between the liquid- and solid-calibrated BMD values. No influence on the cross-calibration due to simulated variations in body size or vertebral fat content was seen, though a significant difference in the cross-calibration was observed between scans acquired at 80 and 140 kVp. From the patient measurements, a linear relationship between the liquid (UCSF) and solid (IA) calibrated values was derived for GE 9800 CT scanners at 80 kVp (IA = [1.15 x UCSF] - 7.32).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2025

Phosphoproteomics delineates hepatocellular carcinoma subtypes and pinpoints therapeutic targets.

BACKGROUND AND AIMS: Only a minority of patients could benefit from systemic therapy owing to the high heterogeneity of HCC. Therefore, a deeper understanding of the pathogenesis of HCC is essential for precision therapy. Genomic and proteomic studies of HCC have enhanced our understanding of HCC. However, the phosphoproteomic characterization of HCC remains poorly understood. APPROACH AND RESULTS: We conducted an in-depth analysis of a clinical cohort of HCC using high-coverage phosphoproteomic. Effective therapeutic targets were validated using liver cancer cell lines and HCC patient-derived xenograft mouse models that correspond to the phosphoproteomic subtypes of HCC. Phosphoproteomic analysis classified HCC into 3 subtypes, A, B, and C, with increasing malignancy and correlation with clinical features, including patient prognosis, tumor staging, serum alpha-fetoprotein levels, tumor thrombus, and tumor size. Phosphoproteomic subtyping deeply reflected the biological characteristics and clinical features of patients with HCC&#x200b;&#x200b;&#x200b;&#x200b;&#x200b;&#x200b;. The profiles of HCC-dysregulated kinase activities inferred from the different phosphoproteomic subtypes consistently identify increased kinase activity related to cell proliferation. Subtype-C HCC patients showed the most significant dysregulation, indicating a potential therapeutic target. The corresponding drug, bosutinib, demonstrated efficacy in inhibiting the growth of subtype C tumors in liver cancer cell lines and HCC patient-derived xenograft mouse models representative of the phosphoproteomic HCC subtypes. CONCLUSIONS: Our study provides a comprehensive exploration of the phosphoproteomic landscape of HCC, establishing new subtypes that match clinical features and identifying potential therapeutic targets for the most malignant C subtype.

Carcinoma, Hepatocellular↗
PubMed2026

MET Exon 14 Skipping Mutation in NSCLC: From Genomic Discovery to Biomarker-Guided Therapeutic Innovation.

INTRODUCTION: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and the MET exon 14 skipping mutation is a key oncogenic driver, which promotes tumor progression and provides a new direction for precision therapy. METHODS: A systematic search of English-language literature and clinical trial data related to the MET exon 14 skipping mutation from 2020-2025 was performed to summarize the role of the mutation and therapeutic advances. RESULTS: DNA-based next-generation sequencing (NGS), RNA-based NGS, and RT-qPCR were employed as the main detection methods. Preclinical models confirmed that mutations promote tumor progression by activating the RAS/MAPK pathway. Clinical trials have reported objective remission rates (ORR) of 46-68% for first-line treatment with MET inhibitors in NSCLC patients harboring MET exon 14 skipping mutations. DISCUSSION: MET exon 14 skipping mutation as a therapeutic target for NSCLC has made significant progress, and MET inhibitors are more advantageous than chemotherapy and immunotherapy, and have been recommended by national and international guidelines as a first-line treatment option. Additionally, NGS technology has the potential to dynamically monitor tumor evolution and drugresistant mutations, thereby helping to realize precision medicine. CONCLUSION: The MET exon 14 skipping mutation is an important target for the precision treatment of NSCLC, and MET-TKIs have remarkable efficacy but a prominent problem with drug resistance. The construction of a precision medicine system encompassing diagnosis, treatment, and drug resistance management through multi-omics research, technological innovation, and international collaboration is a key direction for improving prognosis.

Humans↗
PubMed2004

An anatomico-radiological study of an accessory mandibular foramen on the medial mandibular surface.

Unnamed foramina are known to be present in the mandible. The present research paper reports the presence of an accessory foramen on the medial surface of the mandible, highlighting its anatomico-radiological details. Accessory foramina in the mandible have been known to transmit branches of nerves supplying the roots of the teeth. Nerve block techniques by local anaesthetics might fail if any of these nerves or their branches pass through these accessory foramina and thus escape the nerve block. Dental surgeons performing extractions should be aware of accessory foramina on the mandible and thus plan anaesthesia at an appropriate anatomical site. The presence of such foramina might also be an alternate route for tumour spread following radiation therapy. Precise knowledge and awareness of such accessory mandibular foramina would therefore be important for dental surgeons performing nerve block and also for oncologists in planning radiation therapy.

Humans↗
PubMed2001

Hemolytic uremic syndrome in an adolescent with Fusobacterium necrophorum bacteremia.

Microorganisms may produce substances that disrupt the interaction between platelets and vascular endothelium, which has been associated with atypical hemolytic uremic syndrome (HUS). We present the first reported case of Fusobacterium necrophorum bacteremia that presented initially with atypical HUS. Antimicrobial therapy eradicated the patient's bacteremia, and plasmapheresis restored platelet-endothelial homeostasis. Understanding the pathophysiologic mechanisms involved in atypical HUS would guide the development of more precise therapies.

Adult↗
PubMed1999

Precision and method bias of two assays for oestradiol: consequences for decisions in assisted reproduction.

Oestradiol monitoring in assisted reproduction is empirical, with no proof of benefit. Precise oestradiol estimation will be an essential pre-requisite for high quality evaluation of possible differences between combined and ultrasound-only monitoring. Objectives of the present trial were independent method comparison and bias estimation of chemiluminescent immunoassay (CLIA) versus radioimmunoassay for oestradiol. In a prospective comparison, 505 consecutive samples were split and assayed concurrently. Precision (reproducibility), relative bias and logistics were analysed and compared to manufacturers' findings. Correlation between CLIA and radioimmunoassay was excellent. Positive bias with CLIA necessitated altering decision points for therapy. Precision (reproducibility) was superior with CLIA, making it an appropriate candidate method for future randomized trials of the effectiveness of combined oestradiol/ultrasound monitoring for assisted reproduction.

Decision Making↗
PubMed2004

Bacterial meningitis in Burkina Faso: surveillance using field-based polymerase chain reaction testing.

BACKGROUND: In addition to frequent epidemics of group A meningococcal disease, endemic bacterial meningitis due mostly to Neisseria meningitidis, pneumococcus, and Haemophilus influenzae type b is a serious problem in sub-Saharan Africa. The improved ability to identify the etiologic agent in cases of bacterial meningitis will facilitate more rapid administration of precise therapy. METHODS: To describe the epidemiology of bacterial meningitis and evaluate the usefulness of field-based polymerase chain reaction (PCR) testing, we implemented population-based meningitis surveillance in Burkina Faso during 2002-2003 by use of PCR, culture, and antigen detection tests. RESULTS: Among persons aged 1 month to 67 years, the incidences of meningococcal meningitis, pneumococcal meningitis, and Haemophilus influenzae type b meningitis were 19 cases (n=179), 17 cases (n=162), and 7.1 cases (n=68) per 100,000 persons per year, respectively. Of the cases of meningococcal meningitis, 72% were due to N. meningitidis serogroup W135. Pneumococcal meningitis caused 61% of deaths and occurred in a seasonal pattern that was similar to that of meningococcal meningitis. Of cases of pneumococcal meningitis and N. meningitidis serogroup W135 meningitis, 71% occurred among persons >2 years of age. Most patients, regardless of the etiology of their illness and the existence of an epidemic, received short-course therapy with oily chloramphenicol. Compared with culture as the gold standard, the sensitivity and specificity of PCR in the field were high; this result was confirmed in Burkina Faso and Paris. CONCLUSIONS: Precise and rapid identification of etiologic agents is critical for improvement in the treatment and prevention of meningitis, and, thus, PCR should be considered for wider use in Africa. Vaccines against Streptococcus pneumoniae, N. meningitidis (including serogroup W135), and H. influenzae type b all will have a major impact on the bacterial meningitis burden. Antibiotic recommendations need to consider the importance of S. pneumoniae, even during the epidemic season.

Adolescent↗
PubMed2001

Esophageal cancer.

Accurate pretherapy staging for esophageal cancer is important for stage-directed therapy. Precise staging is also essential for quality control and ensuring the validity of clinical trials. Endoscopic ultrasound is currently the best technique in local regional staging. Various investigators have attempted to overcome the problems of nontraversable lesions and restaging after neoadjuvant therapy. Positron emission tomography scan was shown to be especially useful in identifying distant metastases. Its more widespread use is likely to impact on treatment strategies. Surgical resection remains the mainstay of treatment of esophageal cancer. Improvement in immediate postoperative morbidity, mortality, and long-term survival was shown by various reports to relate to experience and volume. The concept of three-field dissection was further defined by illustrating the importance of lymphadenectomy around the recurrent laryngeal nerves. Multimodality treatments continue to receive attention. Several studies have established the patterns of practice in the United States in treating esophageal cancer. Chemoradiation programs are gaining a more important role and are widely used, although their exact roles are uncertain. Closely related to this area of research is the search of molecular markers of favorable response to such therapies. Concerning palliative treatment for esophageal cancer, self-expanding metallic stents have a definite role in patients with malignant dysphagia. Their results and complications are reviewed. Lastly, quality-of-life issues have assumed more importance in studies in oncology. Prospective quality-of-life data should be evaluated in future studies on different treatment methods for this deadly disease.

Journal Article↗
PubMed1995

Thrombolytic therapy for evolving myocardial infarction needs an approach that integrates benefit and risk.

Thrombolytic therapy is a major step forward in the treatment of acute myocardial infarction and results in substantial reduction of mortality. However, in individual patients the benefits and bleeding risk are difficult to estimate, especially when benefit seems small or outweighed by the risk of intracranial bleeding. For this and other reasons less than half the patients with evolving myocardial infarction are treated with thrombolytic therapy. We propose to approach the decision 'to treat or not to treat' in a systematic way, integrating estimated benefit and intracranial bleeding risk in individual patients. According to a decision-model developed with currently available medical knowledge, thrombolytic therapy appears beneficial in the majority of patients with evolving myocardial infarction provided that ST segment elevation is present and treatment can be started within 12 h of onset of symptoms. Thrombolytic therapy is warranted in the absence of risk factors for intracranial haemorrhage, even if the risk of cardiac death in the first year without thrombolytic therapy is as low as 2.3% (patients with small inferior wall infarctions). For patients with increased intracranial bleeding risk, the cardiac baseline risk without thrombolytic therapy and treatment delay become important variables to take into account when selecting thrombolytic therapy. Precise thresholds for these variables are presented.

Cerebral Hemorrhage↗
PubMed2001

Psoriasis: the future.

The aetiology of psoriasis is still unclear but our knowledge of the psoriatic process has grown substantially over the last two decades. The future will undoubtedly bring advances in our understanding of the pathogenesis of psoriasis and, as a consequence, new therapies. Defining the molecular genetics of psoriasis will enhance our understanding of the disease process and hopefully facilitate the development of a representative animal model. This in itself will be a key step in the development and testing of new therapies. Precise identification of the immunological events involved in psoriasis will allow specific T-cell- and cytokine-targeted, and perhaps less toxic. immunotherapies. Anti-angiogenic agents that are in development for use in oncology may also be effective in psoriasis. The adaptation of current topical therapies such as retinoids and vitamin D analogues to produce more effective and better-tolerated formulations will also play a significant role in our future first-line management of patients. The increased recognition and better management of environmental trigger factors such as psychological distress will become an important factor in future psoriasis care. The development of physical therapies including photodynamic therapy and excimer lasers has the potential to expand the remit of psoriasis therapy. There is little doubt that the future for our patients with psoriasis is bright. However, this will only be achievable by a concerted research effort to understand all facets of this enigmatic disease ranging from the molecular to the environmental.

Angiogenesis Inhibitors↗
PubMed2001

Optimized intensity-modulated arc therapy for prostate cancer treatment.

We recently implemented intensity-modulated arc therapy (IMAT) at our institution. In this study, we evaluate the dosimetric merits of the application of this technique to the treatment of prostate cancer. Each IMAT treatment plan incorporated bilateral overlapping arcs. The dose from each beam segment was computed using the three-dimensional dose model of a clinical treatment planning system (Render Plan 3.5, Precision Therapy). The weights assigned to the individual arc segments were optimized using a gradient search method. For 12 patients, comparisons were made between the IMAT treatment plans and corresponding plans using fixed cone-beam intensity-modulated radiotherapy (IMRT) from a commercial inverse planning system (CORVUS, NOMOS Corp.). We found that the optimized IMAT treatments produced similar dose distributions to the IMRT deliveries. Compared with the IMRT treatments, the IMAT treatments produced slightly less target dose homogeneity with consistently greater sparing of the rectum in regions of lower dose. The trade-off between target dose conformity and rectum sparing can be adjusted in both optimization procedures. Because the total beam-on time for IMAT delivery is 1 to 2 minutes with approximately 5-6 minutes of patient setup time, the delivery efficiency of the IMAT treatment was significantly better than the multiple-beam IMRT treatment.

Humans↗