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The therapeutic effects of many pharmacotherapies have been explored, but disadvantages such as low drug specificity, drug resistance and side effects makes their effective delivery to target sites a great challenge. Consequently, a distinctive prodrug-based technology have emerged as an effective treatments because of their distinctive advantages, such as high drug loading capacity, precise targeting, reduced side effects and spatial and temporal controllability. In particular, the use of gamma/X-ray-mediated strategies in radiotherapy is a new strategy that could enable the precise drug release from implanted devices. This review presents readers with the current state of prodrug therapy and reports the design protocols of rational and effective prodrugs for clinical use., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The aim of this study was to evaluate postmarketing ocrelizumab safety and effectiveness in a real-world population with multiple sclerosis (MS) and matching these parameters among MS disease types., Methods: This was a retrospective, single-center study with MS patients treated with ocrelizumab. Demographic, clinical characteristics and immunological data were analyzed, including annualized relapse rate (ARR), relapse-free rate, Expanded Disability Status Scale (EDSS), complete blood count parameters, immunoglobulin (Ig) levels, liver function tests (LFT), hepatitis markers and adverse events in the 4-year follow-up. A total of 96 patients, 22 with relapsing-remitting MS (RRMS), 54 with secondary progressive MS (SPMS), and 20 with primary progressive MS (PPMS) who were treated with at least two doses of ocrelizumab between January 2018 and September 2023 were included in the study., Results: Sixty-five (68%) were women and 31 (32%) were men. The mean age was 48.4 ± 11.1 years (20-70 years). Ninety-three patients were evaluated in the first year, 65 in the second year, 39 in the third year and 24 in the fourth year of treatment. 96% of patients were relapse-free rate in the first year, 91% in the second year, 85% in the third year and 75% in the fourth year. Eighty-six percent of patients were progression free in the 1st year of treatment, 71% in the 2nd year, in 64% in the 3rd year, and in 62% in the 4th year. During the follow-up of the cases, EDSS remained stable in 77% of RRMS patients, improved in 14%, and worsened in 9%; while EDSS remained stable in 65% of SPMS patients with attacks, it improved in 9% and worsened in 26%; while EDSS remained stable in 60% of PPMS patients, worsening was observed in 40%. There is a significant decrease in IgM and IgG values during the follow-up of ocrelizumab therapy (p < 0.001, p = 0.014). There is no significant difference in IgA, lymphocyte and neutrophil values (p = 0.713, p = 0.086, p = 0.999). No significant relationship was found between low serum IgM levels and the risk of developing infection (p > 0.05). Liver function tests was found to be within normal limits in 94% of the patients over a 4-year period. No hepatitis B, C or A infection, hepatitis B reactivation, tuberculosis, HIV infection, malignancy or drug related death occurred during 4-years follow-up. The most common side effect during ocrelizumab treatment is urinary tract infection (29%); others were upper respiratory tract infections (13%), numbness/tingling of the face, trunk, or extremities (8%), insomnia (6%), headache (5%), and soft tissue infections (cellulitis and dental abscess, 2%)., Conclusions: Our results show that ocrelizumab reduces the frequency of attacks and prevent the disease progression in RRMS patients, and reducing the disease progression by primarily stabilizing EDSS scores in SPMS with attacks and PPMS. It is thought that the relatively high rates of urinary tract infection detected in this study may be related with advanced stage of the disease. The absence of hepatitis B reactivation, chronic infection or malignancy in the 4-year follow-up of our cases supports the long-term safety of ocrelizumab treatment. Ocrelizumab may be preferred as an effective and reliable treatment of different types of MS due to non-serious side effects., (© 2024. The Author(s) under exclusive licence to Belgian Neurological Society.)

KIFC2 plays an important role in prostate cancer progression and chemotherapy resistance, but the mechanism of its involvement in other malignancies remains unclear. Therefore, this study aimed to analyze and validate the mechanism of effect of KIFC2 in multiple tumors. Bioinformatic analysis was performed in conjunction with multiple databases (The Cancer Genome Atlas, Genotype-Tissue Expression Project, Human Protein Atlas, etc.) to fully explore the potential role of KIFC2 within individual tumors and to analyze the correlation with major research components such as prognosis, mutations, and the tumor microenvironment. The expression of KIFC2 demonstrates a significant correlation with the prognosis, clinical phenotype, tumor mutational burden, microsatellite instability, and tumor microenvironment across various malignancies and is associated with the modulation of diverse functional and signaling pathways. The differences in the expression of KIFC2 in the bladder cancer tissues (14 pairs) were statistically significant. The pan-cancer analysis in this study revealed the multifunctionality of KIFC2 in a variety of tumors, indicating a possible prognostic predictor and potential therapeutic target for tumors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Delayed or missed doses are inevitable in epilepsy pharmacotherapy. The current remedial measures recommended by the United States Food and Drug Administration (FDA) for non-adherence are generic and lack clinical evidence., Aim: To assess remedial strategies for delayed or missed pregabalin doses in patients with epilepsy using Monte Carlo simulations., Method: Monte Carlo simulations were performed using a published population pharmacokinetic model for pregabalin. The applicability of five proposed remedial regimens as well as FDA recommendations was evaluated by simulating various poor adherence scenarios in eight populations, including those with renal dysfunction., Results: All proposed remedial strategies were associated with delay duration and renal function. When delays are relatively short, an immediate regular dose is advised. The cut-off time points for taking the regular dose as a remedial regimen were 1, 2, 4, and 12 h for patients with mild renal impairment and normal renal function, moderate renal impairment, severe renal impairment, and end-stage renal disease, respectively. However, when delay aligns closely with a dosing interval, a regular dose combined with a partial dose proves effective. Generally, supplementing 1.3-fold the regular dose at the next scheduled time adequately compensates for the missed dose., Conclusion: Model-based simulations provided quantitative evidence for the effectiveness and feasibility of remedial strategies for missed or delayed pregabalin doses., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

One of the most widespread forms of blood cancer is known as acute myeloid leukemia (AML) which has an incidence of 80% with poor prognosis. Although there are different treatment methods for AML in clinic, the heterogeneity and complexity of the disease show that new treatments are needed. The aim of this study is to investigate the anticancer effects of inhibition of PI3K and HDAC enzymes on CMK and MOLM-13 AML cells lines. We demonstrated that the combination of LY294002 with SAHA and Tubastatin A significantly decreased the cell viability of both cell lines. In contrast, the LY294002 and PCI-34051 combination did not show a significant difference compared to the single LY294002 administration. The combination treatment of LY294002 and HDAC inhibitors did not induce apoptosis significantly. However, LY294002 + SAHA and LY294002 + PCI-34051 resulted in G0/G1 and G2/M cell cycle arrest in CMK cells, respectively. On the other hand, compared to control cells, LY294002 + SAHA and LY294002 + PCI-34051 led to G0/G1 phase arrest in MOLM-13. Furthermore, the LY294002 + PCI-34051 combination elevated the expression rate of LC3BII/I, an autophagy marker, in CMK cells by 2.5-fold. Our study revealed that the combinations of PI3K inhibitor and HDAC inhibitors showed a synergistic effect and caused a reduction in cell viability and increased cell cycle arrest on MOLM-13 and CMK cell lines. In addition, the expression of LC3BII was elevated in the CMK cell line. In conclusion, although more mechanistic studies are required, a combinational inhibition of PI3K and HDAC could be a promising approach for AML., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Gene mutation has been a concern for researchers because it results in genetic variations with base changes in molecular structure. Researchers continue to explore methods to detect gene mutations, which may help in disease diagnosis, medication guidance, and so on. Currently, the detection methods, such as whole-genome sequencing and polymerase chain reaction, have some limitations in terms of cost and sensitivity. Ligase (an enzyme) can recognize base mismatch as a commonly used tool in genetic engineering. Therefore, the ligase-related nucleic acid amplification technology for detecting gene mutations has become a research hotspot. In this study, the main techniques explored for detecting gene mutations included the ligase detection reaction, ligase chain reaction, rolling circle amplification reaction, enzyme-assisted polymerase chain reaction, and loop-mediated isothermal amplification reaction. This review aimed to analyze the aforementioned techniques and mainly present their advantages and disadvantages, sensitivity, specificity, cost, detection time, applications, and so on. The findings may help develop sufficient grounds for further studies on detecting gene mutations., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Osteosarcoma (OS) is the most common primary solid malignant tumour of bone, with rapid progression and a very poor prognosis. Iron is an essential nutrient that makes it an important player in cellular activities due to its inherent ability to exchange electrons, and its metabolic abnormalities are associated with a variety of diseases. The body tightly regulates iron content at the systemic and cellular levels through various mechanisms to prevent iron deficiency and overload from damaging the body. OS cells regulate various mechanisms to increase the intracellular iron concentration to accelerate proliferation, and some studies have revealed the hidden link between iron metabolism and the occurrence and development of OS. This article briefly describes the process of normal iron metabolism, and focuses on the research progress of abnormal iron metabolism in OS from the systemic and cellular levels., (© 2023. The Author(s).)

Background: Unrecognized organ hypoperfusion may cause major postoperative complications with detrimental effects for the patient. The use of Indocyanine Green (ICG) to detect organ hypoperfusion is emerging but the optimal methodology is still uncertain. The purpose of this study was to determine the feasibility of real-time continuous quantitative perfusion assessment with Indocyanine Green (ICG) to monitor organ perfusion during minimally invasive surgery using a novel ICG dosing regimen and quantification software., Method: In this experimental porcine study, twelve subjects were administered a priming dose of ICG, followed by a regimen of high-frequency (1 dose per minute), low-dose bolus injections with weight-adjusted (0.008 mg/kg) ICG allowing for continuous perfusion monitoring. In each pig, one randomly assigned organ of interest [stomach (n = 3), ascending colon (n = 3), rectum (n = 3) and spleen (n = 3)] was investigated with varying camera conditions. Video recording was performed with the 1588 AIM Stryker camera platform and subsequent quantitative analysis of the ICG signal were performed using a research version of a commercially available surgical real-time analysis software., Results: Using a high-frequency, low-dose bolus ICG regimen, fluorescence visualization and quantification in abdominal organs were successful in the stomach (3/3), ascending colon (1/3), rectum (2/3), and the spleen (3/3). ICG accumulation in the tissue over time did not affect the quantification process. Considerable variation in fluorescence signal was observed between organs and between the same organ in different subjects. Of the different camera conditions investigated, the highest signal was achieved when the camera was placed 7.5 cm from the target organ., Conclusion: This proof-of-concept study finds that real-time continuous perfusion monitoring in different abdominal organs using ICG is feasible. However, the study also finds a large variation in fluorescence intensity between organs and between the same organ in different subjects while using a fixed weight-adjusted dosing regimen using the same camera setting and placement., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ultrafiltration (UF) technology using polyvinylidene fluoride (PVDF) membrane has been widely applied to water and wastewater treatment due to its low cost and simple operation process. However, PVDF-based UF membrane always encountered the issue of membrane biofouling that greatly impacted the filtration performance. In this study, we prepare a silver nanoparticle (AgNP)-loaded PVDF (Ag/PVDF) UF membrane by an in-situ photoreduction method to mitigate the membrane biofouling. Different from the previously reported method, AgNPs were synthesized in-situ by a UV photoreduction process, in which Ag + ions were reduced to zero-valent Ag nanoparticles by the photo-induced reducing radicals. Antibacterial experiments showed that the inhibition efficiency of Ag/PVDF membrane to Escherichia coli reached up to ~ 99% after antibacterial treatment for 24 h. In comparison with the pristine PVDF membrane, Ag/PVDF membrane possessed a lower water contact angle (83.7° vs. 38.1°), and its pure water flux increased by 23.7%, and a high bovine serum albumin (BSA) rejection efficiency was maintained. In addition, the high stability of the Ag/PVDF composite membrane was confirmed by the extremely low releasing amount of Ag. This study provides a novel strategy for the preparation of metal nanoparticle-incorporated Ag/PVDF ultrafiltration composite membrane showing favorable antibacterial performance and stability., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Fluid catalytic cracking (FCC) unit is one of the means to lighten heavy oil in refineries, and its regenerated flue gas is also the main source of air pollutants from refinery. However, it is not clear about the type and amount of pollutants discharged from FCC units in China. The emissions of regenerated pollutants in the stack flue gases of three typical FCC units in China were investigated in this study, including a partial regeneration unit without a CO boiler (U1), a partial regeneration unit with a CO boiler (U2), and a full regeneration unit (U3). Different monitoring methods were used to analyze the concentration of sulfur dioxide (SO 2 ) and nitrogen oxides (NO x ), and the results showed that Fourier transform infrared spectroscopy (FTIR) monitoring results of SO 2 and NO x are approximately 10 times and 5 times larger than those of the continuous emission monitoring system (CEMS) data, respectively. Also, the contents of characteristic pollutants such as NH 3 , C 6 H 6 , HCN, C 8 H 8 , C 2 H 4 , CH 4 , and CO were also monitored by FTIR, and the emission factors based on coke burn-off rate and throughput were investigated. The pollutants in U1 exhibited relatively higher contents with the NH 3 , HCN, and C 6 H 6 of 116.99, 71.94, and 56.41 mg/Nm 3 in flue gas, respectively. The emission of regenerated pollutants in U2 and U3 are significantly different from U1. Regeneration processes (including coke properties, operating modes, and presence or absence of CO boilers) affected pollutants' emission factors in varying degrees. At last, reasonable emission factors based on the different FCC regeneration processes contribute to the prediction, assessment, and control for the pollutant emission., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Fluid catalytic cracking (FCC) unit emits a large amount of flue gas, which is a major concern of environmental protection supervision. Wet flue gas desulfurization (WFGD) technologies have been widely used to control the emissions of SO 2 in refineries. In this study, stack tests for pollutants emission of a typical FCC unit were conducted. The emission characteristics of the FCC unit indicated that WFGD would cause a large amount of water vapor in the flue gas, which indirectly leads to large quantities of salt pollutants entrained in the flue gas including ammonium sulfite ((NH 4 ) 2 SO 3 ) and ammonium sulfate ((NH 4 ) 2 SO 4 ). A strong correlation among the concentrations of SO 2 , NH 3 , and H 2 O was observed, and factor analysis shows that these concentrations are dominated by a common factor. It was also found that a mass quantity of NH 4 + and SO 3 2- existed in the condensate water of the flue gas. The TG-MS analysis shows that (NH 4 ) 2 SO 3 , and H 3 , SO 2 , and H 2 O are released as reaction products in the form of gas. Therefore, a part of the NH 3 and SO 2 obtained by Fourier transform infrared spectroscopy (FTIR) monitoring may be derived from the decomposition of (NH 4 ) 2 SO 3 emissions rather than FTIR method itself when monitoring the high-humidity FCC flue gas. Thus, the concentration of H 3 and SO 2 emissions rather than FTIR method itself when monitoring the high-humidity FCC flue gas. Thus, the concentration of H 2 O in the flue gas and the type of sampling process need to be taken into consideration during the monitoring process., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The first aim was to investigate whether there was a mediator role of Internet addiction or uncontrolled/emotional eating on the association between emotion dysregulation and body mass index-standard deviation score (BMI-SDS). The second aim was to detect which of these variables (emotion dysregulation, Internet addiction, and uncontrolled/emotional eating) significantly affect the presence of obesity (OB)., Methods: A total of 123 adolescents (OB (n = 65, 57% of girls, mean age = 15 ± 1.9, BMI percentile between 95 and 99) and healthy control (HC) (n = 58; 53% of girls, mean age = 15.5 ± 1.8, BMI percentile between 1 and 84) aged between 11 and 18 were recruited. Difficulties in Emotion Regulation Scale (DERS) and Internet Addiction Test (IAT) were completed by adolescents. Uncontrolled and emotional eating behaviors were measured by Three Factors Eating Questionnaire (TFE-Q)'s sub-domains., Results: There was no significant direct effect of DERS on BMI-SDS, whereas the indirect effect of DERS on BMI-SDS which was mediated by both IAT and TFE-Q was statistically significant. In logistic regression analysis, an increase by 1 point in DERS total score escalated the odds of being OB by 2%. Moreover, a 22-fold increased risk of OB has been detected in moderate/severe Internet addiction compared to no addiction., Conclusion: This cross-sectional study showed that the association between emotion dysregulation and BMI-SDS was totally mediated by internet addiction and uncontrolled/emotional eating. In addition, emotion dysregulation and Internet addiction were significant determinants of OB. A prospective study is needed to detect the causal relationship between these variables., Level of Evidence: Level III, case-control analytic study., (© 2020. Springer Nature Switzerland AG.)

To identify the importance of IRAK2 kinase activity in TLR-mediated signaling pathways, we constructed a retroviral vector harboring either a mouse IRAK2 gene (IRAK2-WT) or with its mutant with loss of function of its ATP-binding site (IRAK2-KD). Further, we comparatively analyzed for the gain of function and modulations in TLR-mediated signaling pathways in IRAK2 knockout (IRAK2-KO) macrophages upon introduction of the IRAK2-WT retroviral constructs. The pBS/IRAK2-KD with the ATP-binding site mutation in IRAK2 was obtained by using site-specific mutagenesis. The recombinants were identified with appropriate double digestion and sequence analysis. The recombinant vector constructs were transfected by lipofection into phoenix packaging cells. The viral vectors (10 7  cfu/mL) with the construct were allowed to infect IRAK2-KO macrophages. The results showed that IRAK2-WT gene overexpressed in the IRAK2-KO macrophages exhibited a modified IRAK2 expression upon LPS induction. However, the modification was absent with IRAK2-KD construct on LPS stimulation; instead, the IRAK2 protein stability was reduced considerably. The results further show that the LPS-induced effect on the stability of IRAK2 is dependent of IRAK4 stimulation.

Background: Renal ischemia-reperfusion predisposes to acute kidney injury (AKI) and mortality. APAC, mast cell heparin proteoglycan mimetic is a potent dual antiplatelet and anticoagulant inhibiting thrombosis in several vascular models., Methods: Clinically relevant (0.06 and 0.13 mg/kg) and high (0.32 and 7.3 mg/kg) heparin doses of APAC and unfractionated heparin (UFH) were administered i.v. in pharmacological studies. Antithrombotic action of APAC and UFH was assessed with platelet aggregation to collagen, activated partial thromboplastin (APTT) and prothrombin (PT) times. Pharmacodynamics of [ 64 Cu]-APAC or -UFH were monitored by PET/CT. Next, APAC and UFH doses (0.06 and 0.13 mg/kg) were i.v. administered 10 min prior to renal ischemia-reperfusion injury (IRI) in rats., Results: APAC in contrast to UFH inhibited platelet aggregation. During 0.06 and 0.13 mg/kg dose regimens APTT and PT remained at baseline, but at the high APTT prolonged fourfold to sixfold. Overall bio-distribution and clearance of APAC and UFH were similar. After bilateral 30-min renal artery clamping, creatinine, urea nitrogen and neutrophil gelatinase-associated lipocalin concentrations and histopathology indicated faster renal recovery by APAC (0.13 mg/kg). APAC, unlike UFH, prevented expression of innate immune ligand hyaluronan and tubulointerstitial injury marker Kim-1. Moreover, in severe bilateral 1-h renal artery clamping, APAC (0.13 mg/kg) prevented AKI, as demonstrated both by biomarkers and survival. Compatible with kidney protection APAC reduced the circulating levels of vascular destabilizing and pro-inflammatory angiopoietin-2 and syndecan-1. No tissue bleeding ensued., Conclusion: APAC and UFH were similarly eliminated via kidneys and liver. In contrast to UFH, APAC (0.13 mg/kg) was reno-protective in moderate and even severe IRI by attenuating vascular injury and innate immune activation.

Vibrio alginolyticus is a Gram-negative halophilic bacterium and has been recognized as an opportunistic pathogen to both humans and marine animals. So far, most studies have been focused on marine animals and few reports have been aimed at mammals, including human. In this study, we first established a mouse model to understand the pathogenic mechanism of V. alginolyticus infection. After infection via intraperitoneal injection, hematological and liver function indicators were evaluated and serum interleukin (IL)-1β and IL-6 expression were detected by ELISA. Furthermore, we compared the virulence of two V. alginolyticus strains, ATCC17749T and E0666. The results demonstrated that V. alginolyticus infection causes robust lung and liver damage and induces changes in IL-1β, IL-6, hematological, and liver indicators. In addition, the ATCC17749T strain appeared to be more virulent than the E0666 strain. Better understanding of the pathogenic mechanism of V. alginolyticus infection should guide effective prevention and therapy for V. alginolyticus infection.

Since their discovery, cell-penetrating peptides (CPPs) have provided a novel, efficient, and non-invasive mode of transport for various (bioactive) cargos into cells. Despite the ever-growing number of successful implications of the CPP-mediated delivery, issues concerning their intracellular trafficking, significant targeting to degradative organelles, and limited endosomal escape are still hindering their widespread use. To overcome these obstacles, we have utilized a potent photo-induction technique with a fluorescently labeled protein cargo attached to an efficient CPP, TP10. In this study we have determined some key requirements behind this induced escape (e.g., dependence on peptide-to-cargo ratio, time and cargo), and have semi-quantitatively assessed the characteristics of the endosomes that become leaky upon this treatment. Furthermore, we provide evidence that the photo-released cargo remains intact and functional. Altogether, we can conclude that the photo-induced endosomes are specific large complexes-condensed non-acidic vesicles, where the released cargo remains in its native intact form. The latter was confirmed with tubulin as the cargo, which upon photo-induction was incorporated into microtubules. Because of this, we propose that combining the CPP-mediated delivery with photo-activation technique could provide a simple method for overcoming major limitations faced today and serve as a basis for enhanced delivery efficiency and a subsequent elevated cellular response of different bioactive cargo molecules.

Background: It is proposed by International Union Against Cancer (UICC) and American Joint Committee on Cancer (AJCC) that at least 6 lymph nodes (LN) should be removed during resection of esophageal cancer for an accurate N classification. However, large series evidence is needed. The aim of this study is to assess the impact of total number of removed LNs during esophagectomy on UICC-TNM staging and long-term survival., Materials and Methods: The clinicopathological data and follow-up results of 1098 patients with advanced esophageal carcinoma who underwent an esophagectomy were analyzed., Results: The survival experience of group A (removed LNs <6) was worse than that of group B (removed LNs > or = 6). With the stratification analysis according to N and TNM stage, for patients with pN0 cancers, the survival in group A was worse than that in group B (P = .003), while in patients with 1 and > or = 2 positive LNs, the survival experience was similar (P = .919 and .182, respectively). A significant difference in survival in patients at stage IIa was observed between group A and group B (P = .005). However, the survival in patients at stage IIb and stage III was not different between the two groups (P = .302 and 0.108, respectively)., Conclusions: For advanced esophageal carcinoma, if the number of resected LNs per operation is less than 6, an occult positive regional LN might be missed, resulting in an inaccurate N classification. The minimum of 6 LNs removed for esophageal cancer recommended by UICC and AJCC is rational and should be complied with.

Using the novel tissue microarray technique, we studied immunohistochemical expression of cell cycle regulators p53, p21, pRb in 42 grade II oligodendrogliomas, 16 grade III anaplastic oligodendrogliomas, 10 primary and 4 recidive grade II oligoastrocytomas, 10 grade III oligoastrocytomas and 2 other grade II mixed gliomas. The p53 immunopositivity associated with malignant histology of the tumor (p = 0.01, Mann-Whitney test) and high pRb expression (p = 0.015). The p21 score associated strongly with histological grade (p < 0.001). The immunopositive tumors had a significantly higher rate of proliferation (p = 0.021). The p21 immunopositivity correlated positively with p53 immunopositivity: among the 33 p21 immunopositive tumors 30 (91%) were p53 immunopositive and only 3 were p53 immunonegative (p = 0.017). Patients with p21 immunonegative primary tumors had significantly better prognosis: among them 42 of the 46 (91%) survived, whereas only 18 of the 30 patients (60%) with p21 immunopositive primary tumors survived until the follow-up date (p = 0.0017). Statistical significance was reached in multivariate analysis as well (p = 0.01, exp(B) = 5.5). The pRb immunopositive tumors had higher proliferation rate than immunonegative tumors (p = 0.002). In multivariate variance analysis, comparing the effects of different regulatory proteins on cell proliferation, only the amount of pRb expression reached statistical significance (p = 0.004). In conclusion, the expression of p21 in oligodendrocytic tumors seems to be upregulated by p53 expression which rises with cell proliferation and malignancy as in attempt to halt cell cycle but seems to be overrun by other factors. The amount of p21 expression has independent prognostic significance and could be used in diagnosis to help the difficult evaluation of the malignancy potential of oligodendrogliomas and oligoastrocytomas.

Background: Most surgery for benign ovarian mass is now performed laparoscopically. Our purpose was to evaluate the usefulness of laparoscopic ultrasonography (LUS) in these operations., Methods: Forty patients treated by laparoscopic extirpation of a benign ovarian tumor were examined perioperatively using an Aloka 7.5-MHz laparoscopic probe. Findings of preoperative vaginal and perioperative laparoscopic ultrasonography were compared with histologic diagnoses. The accuracy of LUS in localizing the tumor in the ovary and ensuring surgical radicalness was evaluated., Results: LUS enabled correct diagnosis in 34/40 and vaginal ultrasonography in 27/40 cases. Localization of the tumor was possible by LUS in all and visually in 21 ovaries. In 2 patients a radical tumor extirpation was not possible without laparoscopic ultrasonographic guidance., Conclusions: Diagnostic accuracy in LUS is better than in vaginal ultrasonography. LUS facilitates exact tumor localization and can be useful in confirming the radicalness of operation.

Background: Schwannomas occur sporadically or in association with neurofibromatosis 2 (NF2), an autosomal dominant disorder, which predisposes to multiple schwannomas, meningiomas and spinal ependymomas, with bilateral vestibular schwannomas as the classic hallmark. As NF2 and sporadic schwannomas differ in some respect in their clinical and biological behavior we evaluated whether there are any differences in the distribution of genetic aberrations between NF2 and sporadic schwannomas. Our interest was also to verify whether secondary genetic alterations besides the loss of 22q could be detected in schwannomas., Methods: We investigated DNA copy number changes in 25 schwannomas (12 NF2 and 13 sporadic schwannomas) using the comparative genomic hybridization (CGH) technique. Some chromosomal regions were further studied by LOH or FISH analysis., Findings: CGH detected genomic abnormalities in 15 of 25 schwannomas (60%). The most common alteration was loss on 22q, found in 32% (8/25) of schwannomas. No consistent changes were detected in other chromosomal regions. The overall number of genetic aberrations was similar in NF2 and in sporadic schwannomas., Interpretation: Our results support the present view that loss of chromosome 22q harboring the NF2 gene plays a universal role in the pathogenesis of schwannomas without consistent involvement of other chromosomal regions.

Cyclin-dependent kinase 4 inhibitor (CDKN2/p16) is a cell cycle regulatory protein that has been demonstrated to be inactivated by mutations, deletions or transcriptional silencing during pathogenesis of a variety of human malignancies. We studied the correlation of CDKN2/p16 expression with cell proliferation activity and patient survival in 42 oligodendrogliomas and 36 astrocytomas. CDKN2/p16 expression was frequently decreased in grade II and anaplastic oligodendrogliomas (17/42) where lack of CDKN2/p16 protein predicted poor survival (p = 0.0045). In astrocytomas low CDKN2/p16 expression was associated with high histologic malignancy grade (p = 0.002): CDKN2/p16 protein level was decreased in 9 out of 10 glioblastomas, in 5 out of 9 anaplastic astrocytomas, in 3 out of 10 grade II astrocytomas and in none of pilocytic astocytomas (0/7). Low CDKN2/p16 expression was also associated with high cell proliferation activity (MIB-1 immunocytochemistry: p = 0.004; mitotic index: p = 0.007) and poor patient survival (p = 0.025) in astrocytomas. Low CDKN2/p16 mRNA expression had the same topographic distribution as nuclear CDKN2/p16 immunoreactivity proving for reliability of the immunocytochemical findings. Our results are in agreement with earlier studies demonstrating CDKN2/p16 inactivation during tumorigenesis of astrocytic tumors. Furthermore, our findings suggest that loss of CDKN2/p16 expression may also play an important role in the progression of oligodendrogliomas. According to our findings CDKN2/p16 immunocytochemistry could be used as a tool to identify those oligodendrogliomas and low grade astrocytomas that are likely to progress and have poor outcome, and thus would need more aggressive therapy.

We studied whether the high incidence of secondary amyloidosis (SA) is a consistent finding in patients with inflammatory joint disease. A total of 4508 biopsies of patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis were studied at the Rheumatism Foundation Hospital during 1987-1997. The results show that the annual number of findings of SA was reduced from 68 to less than 10. We suggest that a change in medication towards more frequent use of cytostatic agents is the reason for the reduction in incidence of SA.