Predictive Potential of FDG-PET/CT for Histological Transformation in Patients with Indolent Lymphoma

Backgrounds and Purpose—In indolent non-Hodgkin lymphoma, histological transformation is a dramatic event which reduces the prognosis significantly. SUVmax values from FDG-PET/CT help differentiate between aggressive and indolent lymphomas, and transformed indolent lymphomas also show an increased FDG uptake. Possibly FDG uptake increases early in the clinical course and could predict histological transformation. Our objective was to predict histological transformation in indolent lymphomas from initial staging FDG-PET/CT. Patients and Methods—A retrospective study was performed. Patients with biopsy-proven indolent lymphoma who had had initial staging FDG-PET/CT were included. Qualitative (foci compared with FDG uptake liver) and semiquantitative (SUVmax-value per focus) analyses were performed of all abnormal foci. Patient characteristics and outcome were evaluated. Results—We included 88 patients, 5 of whom developed a histological transformation. Semiquantitative analysis showed a relation between maximum standardized uptake value and histological transformation (odds ratio 1.25, 95% CI 1.024 - 1.513). Qualitative analysis showed a negative predictive relation of FDG uptake less than or equal to liver in the occurrence of histological transformation. Transformation-free survival was 100% over 30 months in those with FDG uptake lower than or equal to liver. More FDG uptake than liver showed transformation-free survival of 88% over 30 months. Conclusion—Qualitative analysis of staging FDG-PET/CT in indolent lymphomas could be useful to rule out transformation in the next 30 months. In our study, semiquantitative analysis was statistically significantly associated with histological transformation and maximum standardized uptake value. However, because of the small number of patients, cautious interpretation of the results is warranted. More studies are needed to investigate the role of staging PET/CT in patient with indolent non-Hodkin lymphoma in the prediction of transformation.

Molecular profiling of indolent human prostate cancer： tackling technical challenges to achieve high-fidelity genome-wide data

The contemporary problem of prostate cancer overtreatment can be partially attributed to the diagnosis of potentially indolent prostate cancers that pose low risk to aged men, and lack of sufficiently accurate risk stratification methods to reliably seek out men with indolent diseases. Since progressive acquisition and accumulation of genomic alterations, both genetic and epigenetic, is a defining feature of all human cancers at different stages of disease progression, it is hypothesized that RNA and DNA alterations characteristic of indolent prostate tumors may be different from those previously characterized in the setting of clinically significant prostate cancer. Approaches capable of detecting such alterations on a genome-wide level are the most promising. Such analysis may uncover molecular events defining early initiating stages along the natural history of prostate cancer progression, and ultimately lead to rational development of risk stratification methods for identification of men who can safely forego treatment. However, defining and characterizing indolent prostate cancer in a clinically relevant context remains a challenge, particularly when genome-wide approaches are employed to profile formalin-fixed paraffin-embedded （FFPE） tissue specimens. Here, we provide the conceptual basis underlying the importance of understanding indolent prostate cancer from molecular profiling studies, identify the key hurdles in sample acquisition and variables that affect molecular data derived from FFPE tissues, and highlight recent progresses in efforts to address these technical challenges.

CD8-positive indolent T-Cell lymphoproliferative disorder of the gastrointestinal tract:A case report and review of literature

BACKGROUND Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract(ITLPDGI),a primary tumor forming in the gastrointestinal(GI)tract,represents a rarely diagnosed clonal T-cell disease with a protracted clinical course.CASE SUMMARY This report presented a 45-year-old male patient with a 6-year history of anal fistula and a more than 10-year history of recurrent diarrhea who was not correctly diagnosed until the occurrence of complications such as intestinal perforation.Postsurgical histopathological analysis,combined with hematoxylineosin staining,immunohistochemistry and TCRβ/γ clonal gene rearrangement test,confirmed the diagnosis of CD8+ITLPD-GI.CONCLUSION Individuals with this scarce lymphoma frequently show non-specific symptoms that are hard to recognize.So far,indolent CD8+ITLPD-GI has not been comprehensively examined.The current mini-review focused on evaluating indolent CD8+ITLPD-GI cases based on existing literature and discussing future directions for improved differential diagnosis,detection of genetic and epigenetic alterations,and therapeutic target identification.

A Case of Sinonasal Extranodal NK/T-Cell Lymphoma with Indolent Behaviour and Low-Grade Morphology

Extranodal NK/T-cell lymphoma, nasal type (ENKL), is an uncommon subtype of EBV associated lymphoma usually characterized by aggressive clinical course. We report an atypical sinonasal ENKL case with long-lasting indolent behaviour, developed in the setting of a polymorphic EBV-associated lymphoproliferative disorder (LPD). A 52-year-old woman had suffered from chronic sinusitis and nasal obstruction since 2000, moderately worsened during the last years (marked enlargement of the sino-nasal mucosa at MRI in 2011) with elevated anti-VCA IgG and IgM titers. Three subsequent biopsies revealed slightly increasing morphophenotypic atypia, ranging from a polymorphic B- and T-cell EBV positive proliferation (diagnosed in 2011, but not fulfilling CAEBV diagnostic criteria) to an overt monomorphic mildly atypical T LPD without necrosis and angiocentricty diagnosed as ENKL in 2013 upon immunophenotype and TCR-γ gene clonal rearrangement. Clinically indolent ENKL with low-grade morphology is extremely rare and diagnostically challenging;while the few reports in the literature describe long-survival in ENKL treated patients comparing histologically neoplastic lesions at onset and recurrences, no reports are published on the slow progression from a polymorphic EBV-related T/NK proliferation to a histologically overt clinically indolent ENKL in an untreated patient who only received occasional steroid administration.

Removal of Nitrogen Compounds from Fuels by Deep Eutectic Solvent Based on 1-Butyl-3-Methylimidazolium Bromide and Dicarboxylic Acids

1-Butyl-3-methylimidazolium bromide-based ([Bmim]Br-based) deep eutectic solvents (DESs) can be used aseffective extractants for removing nitrogen compounds from fuel oil. Among the DESs studied, the combination of [Bmim]Brand malonic acid (MA) in a 1:1 molar ratio demonstrated good performance for the removal of both basic and non-basic Ncompounds. The DES [Bmim]Br-MA exhibited extraction efficiencies of 98.4% for quinoline and 92.9% for indole after 30min at 30 ℃ with a DES/oil mass ratio of 1/7. Moreover, the extraction efficiencies remained high at 86.4% for quinolineand 85.9% for indole after recycling the DES four times.. In addition, the DES [Bmim]Br-MA could effectively removeN compounds from Fushun shale diesel oil, with extraction efficiencies of 83.5% for total nitrogen and 89.9% for basicnitrogen at a DES/oil mass ratio of 1/1.

Development and validation of a nomogram to predict indolent course in patients with ulcerative colitis:a single-center retrospective study

Background:The natural disease course for patients with ulcerative colitis(UC)is heterogeneous and few data are available on the indolent course of UC and its related factors.We aimed to develop and validate a nomogramto predict indolent course in patients with UC.Methods:Data of patients diagnosed with UC in the First Affiliated Hospital of Sun Yat-sen University(Guangzhou,China)between April 2007 and February 2021 were retrospectively analysed.Indolent course was defined as a disease course without need for strict interventions(steroids,immunomodulators,biological agents,hospitalization,or surgery therapy)during the follow-up period.The whole cohort was randomly divided into training set and validation set.The nomogram was constructed in the training set based on the results of univariate and multivariate Cox regression analyses.The performance of the nomogram was assessed by the concordance index(C-index),area under the receiver-operating characteristic curve(AUC),and calibration plots.In addition,we internally validated the nomogramvia the bootstrap method and the validation set.Results:Of 969 treatment-naive patients with UC,771(79.6%)had an indolent course after diagnosis.Of these,313 patients were included in the development and validation of the nomogram.The nomogram incorporating age,disease activity,C-reactive protein,and platelet count showed good calibration and discrimination.The C-index was 0.759(0.741 in bootstrap validation)and the AUC at 2,4,and 6 years was 0.767,0.782,and 0.775,respectively.The nomogramperformed well when applied to the validation set.Conclusion:A majority of patients with UC had an indolent course after diagnosis.The nomogram developed in this study might be useful in therapeutic decision-making and follow-up management for patients with UC.

Discovery of prenylated indole alkaloid and natural xanthone from cold-seep sediment derived fungus Talaromyces funiculosus SD-523

A new prenylated indole alkaloid 11,17-epi-mangrovamide A(1),a new natural occurring product,1,7-dihydroxy-6-methyl-8-hydroxymethyl-xanthone(2),two known alkaloids,mangrovamide A(3)and mangrovamide G(4),and four known polyketide derivatives(5–8)were isolated and identified from the cold-seep sediment derived fungal strain Talaromyces funiculosus SD-523.Their structures were elucidated by combination of nuclear magnetic resonance(NMR),high resolution electrospray ionization mass spectroscopy(HRESIMS),quantum chemical electronic circular dichroism(ECD),and DP4+probability analysis as well as by comparison of the data with literature reports.All isolated compounds were tested for antibacterial activities.

The chemical structures and biological activities of indole diterpenoids

Indole diterpenoids(IDTs)are an essential class of structurally diverse fungal secondary metabolites,that generally appear to be restricted to a limited number of fungi,such as Penicillium,Aspergillus,Claviceps,and Epichloe species,etc.These compounds share a typical core structure consisting of a cyclic diterpene skeleton of geranylgeranyl diphos-phate(GGPP)and an indole ring moiety derived from indole-3-glycerol phosphate(IGP).3-geranylgeranylindole(3-GGI)is the common precursor of all IDTs.On this basis,it is modified by cyclization,oxidation,and prenylation to generate a large class of compounds with complex structures.These compounds exhibit antibacterial,anti-insect,and ion channel inhibitory activities.We summarized 204 compounds of IDTs discovered from various fungi over the past 50 years,these compounds were reclassified,and their biological activities were summarized.This review will help to understand the structural diversity of IDTs and provide help for their physiological activities.

Uncarialines A-E,new alkaloids from Uncaria rhynchophylla and their anticoagulant activity

Uncarialines A-E(1-5),five undescribed monoterpene indole alkaloids,together with five known analogues were obtained from the stems of Uncaria rhynchophylla.Alkaloids 1-3 were unique 3,4-seco-tricyclic alkaloids with a 6/5/10 ring system,while 4 and 5 possessed a rare rearranged scaffold originated from corynantheine-type alkaloids with C-2/C-7 oxidation.Their structures were characterized by a comprehensive analysis of MS,NMR,and ECD.Their effects on blood clotting times of human plasma were evaluated and alkaloid 5 had a slight prolongation effect on both thrombin time and activated partial thromboplastin time(p<0.001).

Hepatitis C virus-related B cell subtypes in non Hodgkin's lymphoma

AIM:To evaluate if indolent B cell-non Hodgkin's lymphoma(B-NHL) and diffuse large B-cell lymphoma(DLBCL) in hepatitis C virus(HCV) positive patients could have different biological and clinical characteristics requiring different management strategies.METHODS:A group of 24 HCV related B-NHL patients(11 indolent,13 DLBCL) in whom the biological and clinical characteristics were described and confronted.Patients with DLBCL were managed with the standard of care of treatment.Patients with indolent HCV-related B-NHL were managed with antiviral treatment pegylated interferon plus ribavirin and their course observed.The outcomes of the different approaches were compared.RESULTS:Patients with DLBCL had a shorter duration of HCV infection and a higher prevalence of HCV genotype 1 compared to patients with indolent B-NHL in which HCV genotype 2 was the more frequent genotype.Five of the 9 patients with indolent HCV-relatedB-NHL treated with only antiviral therapy,achieved a complete response of their onco-haematological disease(55%).Seven of the 13 DLBCL patients treated with immunochemotheraphy obtained a complete response(54%).CONCLUSION:HCV genotypes and duration of HCV infection differed between B-NHL subtypes.Indolent lymphomas can be managed with antiviral treatment,while DLBCL is not affected by the HCV infection.

Role of serial multiparametric magnetic resonance imaging in prostate cancer active surveillance

AIM:To examine whether addition of 3T multiparametric magnetic resonance imaging(mp MRI)to an active surveillance protocol could detect aggressive or progressive prostate cancer.METHODS:Twenty-three patients with low risk disease were enrolled on this active surveillance study,all of which had Gleason score 6 or less disease.All patients had clinical assessments,including digital rectal examination and prostate specific antigen(PSA)testing,every 6 mo with annual 3T mp MRI scans with gadolinium contrast and minimum sextant prostate biopsies.The MRI images were anonymized of patient identifiers and clinical information and each scan underwentradiological review without the other results known.Descriptive statistics for demographics and follow-up as well as the sensitivity and specificity of mp MRI to identify prostate cancer and progressive disease were calculated.RESULTS:During follow-up(median 24.8 mo)11 of 23 patients with low-risk prostate cancer had disease progression and were taken off study to receive definitive treatment.Disease progression was identified through upstaging of Gleason score on subsequent biopsies for all 11 patients with only 2 patients also having a PSA doubling time of less than 2 years.All 23 patients had biopsy confirmed prostate cancer but only 10 had a positive index of suspicion on mp MRI scans at baseline(43.5% sensitivity).Aggressive disease prediction from baseline mpM RI scans had satisfactory specificity(81.8%)but low sensitivity(58.3%).Twentytwo patients had serial mp MRI scans and evidence of disease progression was seen for 3 patients all of whom had upstaging of Gleason score on biopsy(30% specificity and 100% sensitivity).CONCLUSION:Addition of mp MRI imaging in active surveillance decision making may help in identifying aggressive disease amongst men with indolent prostate cancer earlier than traditional methods.

Intestinal NK/T cell lymphoma: A case report

BACKGROUND The incidence of intestinal NK/T cell lymphoma(NKTCL)is extremely low,and the clinical symptoms are atypical,which makes it difficult to distinguish this disorder from Crohn's disease(CD),T lymphocyte proliferative disease,and other immune disorders.The misdiagnosis rate is high,and the patient's prognosis is poor.CASE SUMMARY In this case,the patient had repeated high fever,colonoscopy revealed multiple ulcers,and the initial diagnosis was CD.The patient’s condition did not improve after treatment with hormones and infliximab,and she eventually died.Positron emission tomographic-computed tomographic and B-ultrasound were performed in our hospital and showed that multiple lymph nodes were enlarged.Immunohistochemi-stry showed that CD3 and Epstein-Barr virus encoded RNA expression was positive.Colonoscopy,tissue biopsy,and histopathology showed intestinal focal mucosal infiltration of heterotypic lymphocytes with an abnormal immune phenotype.On the basis of the patient’s medical history,auxiliary examination,and pathological findings,digestive physicians and pathologists gave the diagnosis of NKTCL.CONCLUSION Clinicians need to improve their comprehensive knowledge of NKTCL,and combination of clinical symptoms,histological characteristics,as well as colonoscopy biopsies should be considered to improve the diagnosis and thereby reduce misdiagnosis.

Reduced-intensity conditioning allogeneic stem cell transplantation in malignant lymphoma: current status

stem cell transplantation （allo-SCT） is a potential cure for patients with malignant lymphoma that is based on the graft-versus-lymphoma （GVL） effect. Myeloablative conditioning allo-SCT is associated with high mortality and morbidity, particularly in patients older than 45 years, heavily pretreated patients （prior hematopoietic stem cell transplantation or more than two lines of conventional chemotherapy） or patients affected by other comorbidities. Therefore, conventional allo-SCT is restricted to younger patients （〈50 to 55 years） in good physical condition. Over the last decade, allo-SCT with reduced-intensity conditioning （RIC-allo-SCT） has been increasingly used to treat patients with lymphoma. This treatment is associated with lower toxicity and substantial decrease in the incidence of transplant- related mortality, and has the potential to lead to long-term remissions. Therefore, patients who are not suitable to undergo conventional allo-SCT can benefit from the potentially curative GVL effects of allo-SCT. Although RIC-allo-SCT has improved the survival of lymphoma patients, high post-transplant relapse rates or disease progression mainly results in treatment failure. Thus, further improvement is clearly needed. The role and timing of RIC-allo-SCT in the treatment of lymphoma remains unclear. Therefore, more prospective studies should clarify the effectiveness of this method. In this article, we review the recent literature on RIC-alIo-SCT as a treatment for major lymphoma subtypes. Areas that require further investigation in the context of clinical trials are also highlighted.

Studies on the Chemical Constituents of Evodia rutaecarpa Benth

Nine indole alkaloids and one aromatic amine were isolated from Evodia rutaecarpa Benth. Their structures were identified as evodiamine(1),rutaecarpine(2),formyldihydrorutaecarpine(3),goshuyuamide I(4),evodiamide(5),hydroxyevodiamine(6),β carboline(7),1,2,3,4 tetrahydro 1 oxo β carboline(8),dehydroevodiamine(9)and N methylanthranylamide(10).Compound 8 was a new natural product. Compound 7 was for the first time isolated from Evodia.

The Arabidopsis P450 protein CYP82C2 modulates jasmonateinduced root growth inhibition, defense gene expression and indole glucosinolate biosynthesis

Jasmonic acid （JA） is a fatty acid-derived signaling molecule that regulates a broad range of plant defense responses against herbivores and some microbial pathogens. Molecular genetic studies have established that JA also performs a critical role in several aspects of plant development. Here, we describe the characterization of the Arabidopsis mutantjasmonic acid-hypersensitivel-1 （jah1-1）, which is defective in several aspects of JA responses. Although the mutant exhibits increased sensitivity to JA in root growth inhibition, it shows decreased expression of JA-inducible defense genes and reduced resistance to the necrotrophic fungus Botrytis cinerea. Gene cloning studies indicate that these defects are caused by a mutation in the cytochrome P450 protein CYP82C2. We provide evidence showing that the compromised resistance of thejah1-1 mutant to B. cinerea is accompanied by decreased expression of JA-induced defense genes and reduced accumulation of JA-induced indole glucosinolates （IGs）. Conversely, the enhanced resistance to B. cinerea in CYP82C2-overexpressing plants is accompanied by increased expression of JA-induced defense genes and elevated levels of JA-induced IGs. We demonstrate that CYP82C2 affects JA-induced accumulation of the IG biosynthetic precursor tryptophan （Trp）, but not the JA-induced IAA or pathogen-induced camalexin. Together, our results support a hypothesis that CYP82C2 may act in the metabolism of Trp-derived secondary metabolites under conditions in which JA levels are elevated. Thejah1-1 mutant should thus be important in future studies toward understanding the mechanisms underlying the complexity of JA-mediated differential responses, which are important for plants to adapt their growth to the ever-changing environments.

Selective arylation/annulation cascade reactions of 2-alkynylanilines with diaryliodonium salts

An efficient Cu catalyzed selective arylation/annulation cascade reaction of 2-alkynylanilines with diaryliodonium salts was developed.This reaction was selective to N-arylation instead of C-arylation,which provides a simple synthetic method for N-aryl indoles.

Stress kinase inhibition modulates acute experimental pancreatitis

AIM: To examine the role of p38 during acute experimental cerulein pancreatitis. METHODS: Rats were treated with cerulein with or without a specific JNK inhibitor (CEP1347) and/or a specific p38 inhibitor (SB203580) and pancreatic stress kinase activity was determined. Parameters to assess pancreatitis included trypsin, amylase, lipase, pancreatic weight and histology. RESULTS: JNK inhibition with CEP1347 ameliorated pancreatitis, reducing pancreatic edema. In contrast, p38 inhibition with SB203580 aggravated pancreatitis with higher trypsin levels and, with induction of acinar necrosis not normally found after cerulein hyperstimulation. Simultaneous treatment with both CEP1347 and SB203580 mutually abolished the effects of either compound on cerulein pancreatitis. CONCLUSION: Stress kinases modulate pancreatitis differentially. JNK seems to promote pancreatitis development, possibly by supporting inflammatory reactions such as edema formation while its inhibition ameliorates pancreatitis. In contrast, p38 may help reduce organ destruction while inhibition of p38 during induction of cerulein pancreatitis leads to the occurrence of acinar necrosis.

Structural characterization of monoterpene indole alkaloids in ethanolic extracts of Rauwolfia species by liquid chromatography with quadrupole time-of-flight mass spectrometry

Rauwolfia species(Apocynaceae) are medicinal plants well known worldwide due to its potent bioactive monoterpene indole alkaloids(MIAs) such as reserpine,ajmalicine,ajmaline,serpentine and yohimbine.Reserpine,ajmalicine and ajmaline are powerful antihypertensive,tranquilizing agents used in hypertension.Yohimbine is an aphrodisiac used in dietary supplements.As there is no report on the comparative and comprehensive phytochemical investigation of the roots of Rauwolfia species,we have developed an efficient and reliable liquid chromatography-tandem mass spectrometry(LC–MS/MS) method for ethanolic root extract of Rauwolfia species to elucidate the fragmentation pathways for dereplication of bioactive MIAs using highperformance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry(HPLC–ESI–QTOF–MS/MS) in positive ion mode.We identified and established diagnostic fragment ions and fragmentation pathways using reserpine,ajmalicine,ajmaline,serpentine and yohimbine.The MS/MS spectra of reserpine,ajmalicine,and ajmaline showed C-ring-cleavage whereas E-ring cleavage was observed in serpentine via Retro Diels Alder(RDA).A total of 47 bioactive MIAs were identified and characterized on the basis of their molecular formula,exact mass measurements and MS/MS analysis.Reserpine,ajmalicine,ajmaline,serpentine and yohimbine were unambiguously identified by comparison with their authentic standards and other 42 MIAs were tentatively identified and characterized from the roots of Rauwolfia hookeri,Rauwolfia micrantha,Rauwolfia serpentina,Rauwolfia verticillata,Rauwolfia tetraphylla and Rauwolfia vomitoria.Application of LC–MS followed by principal component analysis(PCA) has been successfully used to discriminate among six Rauwolfia species.