Introduction:Butyrophilins(BTNs)belong to the immunoglobulin superfamily;they play crucial roles in immune regulation,especially inγδ T cell activation.While their expression has been studied in solid tumours,their ...Introduction:Butyrophilins(BTNs)belong to the immunoglobulin superfamily;they play crucial roles in immune regulation,especially inγδ T cell activation.While their expression has been studied in solid tumours,their involvement in hematologic malignancies remains poorly understood.Objectives:We hypothesised that BTNs are dysregulated in chronic lymphocytic leukaemia(CLL),contributing toγδT cell dysfunction and potentially influencing disease progression.Methods:In this study,we analyzed publicly available microarray and RNA-seq datasets to investigate the expression patterns of BTN genes in CLL.Results:Our findings reveal significant dysregulation of BTN gene expression in CLL,with BTN2A1,BTN3A1,BTN3A2,and BTN3A3 being markedly downregulated in peripheral blood mononuclear cells(PBMCs)and bone marrow samples from CLL patients compared to healthy volunteers,while BTN1A1 was upregulated.Furthermore,BTN2A2 was selectively downregulated in neoplastic B cells,whereas BTN3A1 was upregulated in T cells from CLL patients compared to healthy volunteers.Notably,lower BTN expression was associated with an unmutated IGVH status and male sex.Kaplan-Meier survival analysis demonstrated that higher expression of BTN2A1,BTN3A1,BTN3A2,and BTN3A3 correlated with a significantly longer overall survival.Conclusions:Given the established role of BTN2A1 and BTN3A1 in the phosphoantigen-mediated activation of Vδ2γδ T cells,their downregulation may contribute toγδ T cell dysfunction in CLL.These results highlight the potential prognostic value of BTN gene expression in CLL and underscore the need for further studies exploring its mechanistic role in disease progression and immune evasion.展开更多
BACKGROUND Hepatic manifestations in chronic lymphocytic leukemia(CLL)are common:Elevation of liver enzymes frequently occurs,and differential diagnosis is often challenging.Liver infiltration by leukemic cells,primar...BACKGROUND Hepatic manifestations in chronic lymphocytic leukemia(CLL)are common:Elevation of liver enzymes frequently occurs,and differential diagnosis is often challenging.Liver infiltration by leukemic cells,primary and secondary hepatic malignancies,drug-induced hepatotoxicity,immunological disorders,and infections have been reported.Nevertheless,syncytial giant cell hepatitis(GCH)as a manifestation of autoimmune hepatitis in patients with CLL is an extremely rare condition,currently reported only in anecdotal cases.CASE SUMMARY Here,we report the case of a 62-year-old Caucasian woman affected by CLL,who developed GCH with peculiar histopathological features.The patient was evaluated for abnormal liver test results.Liver histology revealed significant inflammatory lymphomononuclear infiltrates with a plasma cell component,widespread syncytial changes in the hepatocytes with gigantocellular features,hepatocyte rosettes,and the typical feature of emperipolesis,consistent with a diagnosis of GCH.The patient was treated with corticosteroids and mycophenolate mofetil,resulting in a complete biochemical response.CONCLUSION Early histological diagnosis of GCH is crucial in patients with CLL,with mycophenolate mofetil representing a promising treatment option.展开更多
BACKGROUND Although previous findings indicated that pathological assessment of tumor budding(TB),desmoplastic reaction(DR),and tumor-infiltrating lymphocytes(TILs)may play a role in determining tumor behavior in many...BACKGROUND Although previous findings indicated that pathological assessment of tumor budding(TB),desmoplastic reaction(DR),and tumor-infiltrating lymphocytes(TILs)may play a role in determining tumor behavior in many malignancies,the relationship between TB,DR,and TILs in patients with pancreatic ductal adenocarcinoma(PDAC)is still unknown.AIM To evaluate relationships of TB,DR,and TILs with histopathological parameters and determine their prognostic value in patients with PDAC.METHODS The study cohort comprised 100 patients diagnosed with PDAC.Peritumoral budding(PTB)and intratumoral budding(ITB)were assessed according to the International Tumor Budding Consensus Conference guidelines.DR was classified based on stromal maturation.TILs were evaluated semiquantitatively with a 5%cutoff.Additionally,cases were categorized into two groups according to lymphocyte density:No/Low lymphocytes and medium/high lymphocytes.RESULTS A significant correlation was observed between ITB and PTB(r=0.890).Higher PTB was associated with fewer TILs and immature stroma(P<0.001).PTB and TILs were significantly related to tumor dimension,lymphovascular invasion,lymph node metastasis(LNM),and stage(P<0.005).ITB was also associated with the presence of lymph node involvement.The results of the univariate analysis revealed a significant correlation between poor survival rates and the presence of lymphovascular invasion,LNM,PTB,ITB,and TILs according to scoring(P<0.001).The multivariate analysis revealed LNM,PTB,ITB,and TILs according to scoring as independent prognostic factors.CONCLUSION TB assessment stratified patients with PDAC.PTB-ITB correlation showed diagnostic relevance of ITB in biopsy specimens.The prognostic significance of DR and interplay with TIL subsets warrant further investigation.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is the most prevalent type of pan-creatic neoplasm.It is a highly aggressive lethal malignancy related to its delayed in diagnosis and limited response to treatments.The incidence...Pancreatic ductal adenocarcinoma(PDAC)is the most prevalent type of pan-creatic neoplasm.It is a highly aggressive lethal malignancy related to its delayed in diagnosis and limited response to treatments.The incidence and mortality of pancreatic cancer have been increasing over the years.Tumor budding is a proven independent,adverse prognostic factor in PDAC.It is helpful for improvement of prognosis in PDAC in early and precise diagnostic modalities.Tumor budding should be conveyed in pathology reports and taken into account by future onco-logic staging systems.展开更多
AIM： TO investigate colonic endocrine cells in lympho- cytic colitis （LC） patients. METHODS： Fifty-seven patients with LC were in- cluded. These patients were 41 females and 16 males, with an average age of 49 yea...AIM： TO investigate colonic endocrine cells in lympho- cytic colitis （LC） patients. METHODS： Fifty-seven patients with LC were in- cluded. These patients were 41 females and 16 males, with an average age of 49 years （range 19-84 years）. Twenty-seven subjects that underwent colonoscopy with biopsies were used as controls. These subjects underwent colonoscopy because of gastrointestinal bleeding or health worries, where the source of bleed- ing was identified as haemorrhoids or angiodysplasia. They were 19 females and 8 males with an average age of 49 years （range 18-67 years）. Biopsies from the right and left colon were obtained from both patients and controls during colonoscopy. Biopsies were fixed in 4% buffered paraformaldehyde, embedded in paraffin and cut into 5 μm-thick sections. The sections immunostained by the avidin-biotin-complex method for se- rotonin, peptide YY （PYY）, pancreatic polypeptide （PP） enteroglucagon and somatostatin cells. The cell densi- ties were quantified by computerised image analysis using Olympus software. RESULTS： The colon of both the patient and the control subjects were macroscopically normal. Histo- pathological examination of colon biopsies from con- trols revealed normal histology. All patients fulfilled the diagnosis criteria required for of LC： an increase in intraepithelial lymphocytes （〉 20 lymphocytes/100 epithelial cells） and surface epithelial damage with increased lamina propria plasma cells and absent or minimal crypt architectural distribution. In the colon of both patients and control subjects, serotonin-, PYY-, PP-, enteroglucagon- and somatostatin-immunoreac- tive cells were primarily located in the upper part of the crypts of Lieberk0hn. These cells were basket- or flask-shaped. There was no statistically significant dif- ference between the right and left colon in controls with regards to the densities of serotonin- and PYY- immunoreactive cells （P = 0.9 and 0.1, respectively）. Serotonin cell density in the right colon in controls was 28.9 ± 1.8 and in LC patients 41.6±2.6 （P = 0.008）. In the left colon, the corresponding figures were 28.5± 1.9 and 42.4± 2.9, respectively （P = 0.009）. PYY cell density in the right colon of the controls was 10.1 ± 1 and of LC patients 41 ± 4 （P = 0.00006）. In the left colon, PYY cell density in controls was 6.6± 1.2 and in LC patients 53.3 ± 4.6 （P = 0.00007）. CONCLUSION： The change in serotonin cells could be caused by an interaction between immune cells and serotonin cells, and that of PYY density might be sec- ondary.展开更多
Chronic lymphocytic leukemia(CLL) is the most common leukemia in the western world. Despite significantadvances in therapy over the last decade CLL remains incurable. Current front-line therapy often consists of chemo...Chronic lymphocytic leukemia(CLL) is the most common leukemia in the western world. Despite significantadvances in therapy over the last decade CLL remains incurable. Current front-line therapy often consists of chemoimmunotherapy-based regimens, most commonly the fludarabine, cyclophosphamide plus rituximab combination, but rates of relapse and refractory disease are high among these patients. Several key signaling pathways are now known to mediate the survival and proliferation of CLL cells in vivo, the most notable of which are the pathways mediated by the B-cell receptor(BCR) and cytokine receptors. A better understanding of the pathogenesis of the disease, the underlying biology of the CLL-cell and the roles of the tumour microenvironment has provided the rationale for trials of a range of novel, more targeted therapeutic agents. In particular, clinical trials of ibrutinib and idelalisib, which target the Brutons tyrosine kinase and the delta isoform of phosphoinositol-3 kinase components of the BCR signaling pathway respectively, have shown extremely promising results. Here we review the current literature on the key signaling pathways and interactions of CLL cells that mediate the survival and proliferation of the leukemic cells. For each we describe the results of the recent clinical trials and in vitro studies of novel therapeutic agents.展开更多
Objective： This study aims to evaluate the natural history of patients with chronic lymphocytic leukemia （CLL） and a 17p deletion （17p-） and identify the predictive factors within this subgroup. Methods： The sam...Objective： This study aims to evaluate the natural history of patients with chronic lymphocytic leukemia （CLL） and a 17p deletion （17p-） and identify the predictive factors within this subgroup. Methods： The sample of patients with CLL were analyzed by fluorescence in situ hybridization for deletions in chromosome bands 1 lq22, 13q14 and 17p13; trisomy of bands 12q13; and translocation involving band 14q32. The data from 456 patients with or without a 17p- were retrospectively collected and analyzed. Results： The overall response rate （ORR） in patients with a 17p- was 56.9%, and patients with a high percentage of 17p- （defined as more than 25% of cells harbouring a 17p-） had a lower ORR. The median overall survival （OS） in patients with a 17p- was 78.0 months, which was significantly shorter than the OS in patients without this genetic abnormality （median 162.0 months, P〈0.001）. Within the subgroup with a 17p-, the progression-free survival was significantly shorter in patients at Binet stage B-C and patients with elevated lactate dehydrogenase （LDH）, B symptoms, unmutated IGHVand a high percentage of 17p-. Conclusions： These results indicated that patients with a 17p- CLL have a variable prognosis that might be predicted using simple clinical and laboratory characteristics.展开更多
Lymphocytic esophagitis (LE) is a clinicopathologic entity first described by Rubio et al in 2006. It is defined as peripapillary intraepithelial lymphocytosis with spongiosis and few or no granulocytes on esophageal ...Lymphocytic esophagitis (LE) is a clinicopathologic entity first described by Rubio et al in 2006. It is defined as peripapillary intraepithelial lymphocytosis with spongiosis and few or no granulocytes on esophageal biopsy. This definition is not widely accepted and the number of lymphocytes needed to make the diagnosis varied in different studies. Multiple studies have described potential clinical associations and risk factors for LE, such as old age, female gender and smoking history. This entity was reported in inflammatory bowel disease in the pediatric population but not in adults. Other associations include gastroesophageal reflux disease and primary esophageal motility disorders. The most common symptom is dysphagia, with a normal appearing esophagus on endoscopy, though esophageal rings, webs, nodularities, furrows and strictures have been described. Multiple treatment modalities have been used such as proton pump inhibitors and topical steroids. Esophageal dilation seems to be therapeutic when dysphagia is present along with esophageal narrowing secondary to webs, rings or strictures. The natural history of the disease remains unclear and needs to be better delineated. Overall, lymphocytic esophagitis seems to have a chronic and benign course, except for two cases of esophageal perforation in the literature, thought to be secondary to this entity.展开更多
AIM： To find out the role of bacteria as a possible etiological factor in lymphocytic colitis. METHODS： Twenty patients with histopathological diagnosis of lymphocytic colitis and 10 normal controls were included in...AIM： To find out the role of bacteria as a possible etiological factor in lymphocytic colitis. METHODS： Twenty patients with histopathological diagnosis of lymphocytic colitis and 10 normal controls were included in this study. Colonoscopic biopsies were obtained from three sites （hepatic and splenic flexures and rectosigmoid region）. Each biopsy was divided into two parts. A fresh part was incubated on special cultures for bacterial growth. The other part was used for the preparation of histologic tissue sections that were examined for the presence of bacteria with the help of Giemsa stain. RESULTS： Culture of tissue biopsies revealed bacterial growth in 18 out of 20 patients with lymphocytic colitis mostly Escherichia coil （14/18）, which was found in all rectosigmoid specimens （14/14）, but only in 8/14 and 6/14 of splenic and hepatic flexure specimens respectively. In two of these cases, E coli was associated with proteus. Proteus was found only in one case, Klebsiella in two cases, and Staphylococcus aureus in one case. In the control group, only 2 out of 10 controls showed the growth of E coli in their biopsy cultures. Histopathology showed rod-shaped bacilli in the tissue sections of 12 out of 14 cases with positive E coli in their specimen＇s culture. None of the controls showed these bacteria in histopathological sections. CONCLUSION： This preliminary study reports an association between E coli and lymphocytic colitis, based on histological and culture observations. Serotyping and molecular studies are in process to assess the role of E coli in the pathogenesis of lymphocytic colitis.展开更多
Chemoimmunotherapy(CIT)is defined as standard first line treatment for chronic lymphocytic leukemia(CLL)patients while patients with unfavorable biological characteristics such as unmutated immunoglobulin heavy chain(...Chemoimmunotherapy(CIT)is defined as standard first line treatment for chronic lymphocytic leukemia(CLL)patients while patients with unfavorable biological characteristics such as unmutated immunoglobulin heavy chain(UM-IGHV)and TP53 aberration failed to benefit from it.The emergency of the small molecular targeted agents including Bruton’s tyrosine kinase(BTK)inhibitor(BTKi)leads to a brand-new era,from a CIT to a chemo-free era in CLL.However,the treatment of target agents is not enough to attain a deep remission and high rate of complete remission(CR),especially in patients with high risks.The long duration brought about problems,such as cost,drug resistance and toxicity.To benefit CLL in progression free survival(PFS)and long-term remission,exploration of time-limited therapies,mainly with BTKi plus CIT and BCL2i based combination therapy has become a mainstream in clinical trials.The time-limited combination therapy shed light on the promising potentiality to attain sustainable deep remission and partly overcame the risk factors,although long term follow-up is required to consolidate the conclusion.In this review,we intend to introduce key results of clinical trials with combination therapy,discuss the achievements and limitations and put forward future direction for clinical trial design in this field.展开更多
BACKGROUND The concurrence of acute myeloid leukemia(AML)and chronic lymphocytic leukemia(CLL)is rare.Previous reports of such cases have focused mainly on clinical diagnosis and characteristics,so the mechanism remai...BACKGROUND The concurrence of acute myeloid leukemia(AML)and chronic lymphocytic leukemia(CLL)is rare.Previous reports of such cases have focused mainly on clinical diagnosis and characteristics,so the mechanism remains unclear,and therapy options have been poorly explored.CASE SUMMARY Here,we report two cases of synchronous AML and CLL.Flow cytometry revealed two distinct abnormal cell populations(myeloblasts and lymphoid cells)according to scatter characteristics.CD5-positive B cell lymphoma with myeloid leukemia invasion was observed on lymph node biopsy.Chemotherapy regimens indicated for both AML and CLL were used in our patients,and our patients achieved complete response after chemotherapy.Next-generation sequencing of 88 genes was performed.CONCLUSION We conclude that early mutation and dysregulation at the hematopoietic stem cell stage and the accumulation of multiple rearrangements may cause the concurrence of CLL and AML.The treatment of infection and combination therapy aimed at the CLL component are significant in the management of patients with concurrent CLL and AML.展开更多
We describe a patient with concomitant B-cell chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). CLL- and MM-cell were separated by preparative flourescence-activated cell sorting (FACS). DNA sequence analy...We describe a patient with concomitant B-cell chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). CLL- and MM-cell were separated by preparative flourescence-activated cell sorting (FACS). DNA sequence analysis of the complementarity-determinining region III (CDR III) of the immunoglobulin heavy chain genes showed identical gene rearrangements in the CLL- and the MM-cell population. Our findings prove a common clonal tumor origin of both B-cell diseases in this patient.展开更多
Using Southern blot, Northern blot and Quick blot methods, we examined the rearrangement and expression of TCR βgene in four early differentiation stage cell lines from human hemopoietic system, namely HL-60, Jurkat,...Using Southern blot, Northern blot and Quick blot methods, we examined the rearrangement and expression of TCR βgene in four early differentiation stage cell lines from human hemopoietic system, namely HL-60, Jurkat, Daudi and Raji cells as well as lymphocytes from 17 acute lymphocytic leukemia （ALL） patients. The results showed. Ⅰ) Rearrangement of TCR βgene was seen in Jurkat cells. A germline pattern was observed in HL-60, Daudi and Raji cells. 2) Eight of 9 patients with T-ALL had cells with rearranged TCR βgene. But two of 3 patients with B-ALL and three of 5 patients with nonT, nonB-ALL also had cells with rearranged TCR βgene. 3) A 1.3 kb full-length transcript and a 1.0 kb truncated transcript were detected in Jurkat cells by probing with <sup>32</sup>P-TCR βcDNA. But some leukemic B cells also expressed an incompleted transcript. 4) TCR βmRNA was detected in six of 8 patients with T-ALL, four of 5 patients with nonT, nonB-ALL and one of 3 patients with B-ALL. But the level of expression was quite differ ent. The dual-rearrangement and the abnormal expression may give us a new clue for researching leukemogenesis.展开更多
BACKGROUND Lymphocytic hypophysitis(LYH)is an important condition to consider in the differential diagnosis of patients with a pituitary mass.The main clinical manifestations of LYH include headache,symptoms related t...BACKGROUND Lymphocytic hypophysitis(LYH)is an important condition to consider in the differential diagnosis of patients with a pituitary mass.The main clinical manifestations of LYH include headache,symptoms related to sellar compression,hypopituitarism,diabetes insipidus and hyperprolactinemia.Headache,which is a frequent complaint of patients with LYH,is thought to be related to the occupying effect of the pituitary mass and is rapidly resolved with a good outcome after timely and adequate glucocorticoid treatment or surgery.CASE SUMMARY Here,we report a patient with LYH whose initial symptom was headache and whose pituitary function assessment showed the presence of secondary hypoadrenalism,central hypothyroidism and hypogonadotropic hypogonadism.Pituitary magnetic resonance imaging showed symmetrical enlargement of the pituitary gland with suprasellar extension in a dumbbell shape with significant homogeneous enhancement after gadolinium enhancement.The size of the gland was approximately 17.7 mm×14.3 mm×13.8 mm.The pituitary stalk was thickened without deviation,and there was an elevation of the optimal crossing.The lesion grew bilaterally toward the cavernous sinuses,and the parasternal dural caudal sign was visible.The patient presented with repeatedly worsening and prolonged headaches three times even though the hypopituitarism had fully resolved after glucocorticoid treatment during this course.CONCLUSION This rare headache regression suggests that patients with chronic headaches should also be alerted to the possibility of LYH.展开更多
Determination of minimal residual disease (MRD) remains crucial for the follow-up after therapy in chronic lymphocytic leukemia (CLL) patients. Chimerism was assessed by short tandem repeat (STR)-PCR and single nucleo...Determination of minimal residual disease (MRD) remains crucial for the follow-up after therapy in chronic lymphocytic leukemia (CLL) patients. Chimerism was assessed by short tandem repeat (STR)-PCR and single nucleotide polymorphisms (SNP)-PCR, and MRD by a multicolor flow cytometric approach in 12 consecutive patients with CLL after they received allogeneic stem cell transplantation (SCT). Overall, 11 patients achieved MRD flow negativity [10 had full donor chimerism (FDC) and one had mixed chimerism (MC)]. Only one patient remained with MRD flow positivity and displayed MC. Fifty-six samples were concomitantly studied by both chimerism and MRD flow. A significant correlation was observed between MRD flow data and chimerism in both PB and BM by using a mixed effect linear regression (p < 0.001). Flow cytometry approach of MRD can be easily combined with chimerism during the follow-up post-allogeneic SCT. Both techniques appeared complementary for guiding post-transplant immunomodulation.展开更多
Papular mycosis fungoides(MF) is a rare presentation of MF. Six illustrative cases of papular MF were retrospectively reviewed. Five of the cases studied by immunohistochemistry had variable numbers(range: 1%-20%) of ...Papular mycosis fungoides(MF) is a rare presentation of MF. Six illustrative cases of papular MF were retrospectively reviewed. Five of the cases studied by immunohistochemistry had variable numbers(range: 1%-20%) of CD30+ cells in the dermal infiltrate, a finding that is characteristic of lymphomatoid papulosis but may occasionally occur in typical early MF. Although none of our papular MF patients had progressive disease, lesions with relatively high numbers of CD30+ cells in 3 patients did not respond well to skin-directed treatments used for MF. Interestingly, these patients had evidence of coexisting clonal B cell populations in the blood(one with clonal B cell lymphocytosis and two with B-cell chronic lymphocytic leukemia). We conclude that:(1) papular MF may contain CD30+ cells, thereby causing confusion with lymphomatoid papulosis; and(2) papular MF, like more typical MF, may be associated with clonal B-cell proliferations including chronic lymphocytic leukemia.展开更多
Previous studies have shown that the bcl-2protooncogene encodes a mitochondrial protein thatpromotes cell survival by blocking programmed celldeath. High levels of bcl-2 expression were found inmurine myeloid leukemic...Previous studies have shown that the bcl-2protooncogene encodes a mitochondrial protein thatpromotes cell survival by blocking programmed celldeath. High levels of bcl-2 expression were found inmurine myeloid leukemic cell lines resistant to apoptosisinduced by variety of agents. In addition artificialelevation of bcl-2 expression in a human pre-B leukemiccell line resulted in enhanced resistance to chemo-therapcutic drugs. We reported here on the effect ofbcl-2 antisense phosphorothiate展开更多
Curcumin is a widely researched natural product and is known to possess anticarcinogenic properties.Chronic lymphocytic leukemia is a type of leukemia that principally affects patients with age higher than 60 years.Si...Curcumin is a widely researched natural product and is known to possess anticarcinogenic properties.Chronic lymphocytic leukemia is a type of leukemia that principally affects patients with age higher than 60 years.Since the toxicity of conventional drugs exceeds the benefits of treating this leukemia type,patients are treated only in the advanced symptomatic stages.The current article reviews curcumin,its general actions and targets in cancer,and specifically that of it in chronic lymphocytic leukemia.展开更多
AIM To evaluate the potential association between mild duodenal damage and microscopic colitis(MC).METHODS We retrospectively included 105 consecutive patients with type I Marsh-Oberhuber duodenal damage and negativit...AIM To evaluate the potential association between mild duodenal damage and microscopic colitis(MC).METHODS We retrospectively included 105 consecutive patients with type I Marsh-Oberhuber duodenal damage and negativity for immunoglobulin A anti-endomysium and anti-tissue transglutaminase.The following parameters were analyzed:Sex,age at execution of esophagogastroduodenoscopy,duodenal damage,and number of intraepithelial lymphocytes at biopsies,prevalenceof Helicobacter pylori infection,age at execution of colonoscopy,macroscopic and microscopic features of colonoscopy,family history of gastrointestinal and autoimmune diseases,smoking habits,biochemical parameters of inflammation and autoimmunity,use of proton pump inhibitors or nonsteroidal anti-inflammatory drugs,adverse reactions to drugs or foods,pathologies known to be associated with celiac disease or MC,living on a gluten-free diet or on a gluten-low diet for at least 1 mo.RESULTS Colonoscopy was performed in 59 patients,but only in 48 of them biopsies were taken in the entire colon.Considering the latter cohort,the diagnosis of MC was met in 25(52.1%) patients while in 18 patients other pathologic findings were reported:13(27%) cases of nonspecific inflammatory bowel disease,2(4.2%) cases of Crohn's disease,2(4.2%) cases of eosinophilic gastroenteritis,and 1(2.1%) case of autoimmune enteritis.Five(10.4%) patients had a normal colonoscopic result.Matching the groups by age,and considering only patients who underwent colonoscopy(42.7 ± 15.5 years) vs those who did not undergo colonoscopy(36.9 ± 10.6 years),a statistical difference was found(P = 0.039).Focusing on symptoms,diarrhea was statistically more prevalent in MC group than in patients who did not undergo colonoscopy(P = 0.03).CONCLUSION Mild duodenal damage is associated with MC in more than half of the cases.This association supports the hypothesis of a link between these two entities.展开更多
Objective: To analysis the uptake of free MTX and MTX conjugated to tumor specific monoclonal antibody by target and nontarget cells. Methods: The folate antagonist methotrexate (MTX) was conjugated to two monoclonal ...Objective: To analysis the uptake of free MTX and MTX conjugated to tumor specific monoclonal antibody by target and nontarget cells. Methods: The folate antagonist methotrexate (MTX) was conjugated to two monoclonal antibodies (Mab) directed against human chronic lymphocytic leukemia (CLL), Dal B01 and Dal B02, by an active ester method. Both conjugates were more cytotoxic toward the target tumor cell line D101 than to the nontarget cell line MOLT3, and Dal B02MTX conjugate was more inhibitory to D101 cells than free MTX in a 6 h pulse exposure assay. Results: Drug uptake studies revealed that D101 cells took up much more Dal B01 and Dal B02conjugated MTX than free MTX. The amounts of drug taken up by D101 cells incubated with Dal B01 and Dal B02conjugated MTX were always 3 to 5fold higher than that taken up by MOLT3 cells, although the latter took up more drug when incubated with free MTX. Furthermore, tumor cells incubated with Dal B01 or Dal B02conjugated MTX retained much larger amounts of drug for a prolonged period of time than those incubated with free MTX. Conclusion: The enhanced specific cytotoxicity of Dal B01 and Dal B02MTX conjugates toward target tumor cells is therefore likely due to (I) delivery of larger amounts of MTX to target cells when the drug is conjugated to Mab; (ii) longer retention of Mabconjugated MTX by target cells; and (iii) slow, prolonged release of MTX from the surfacebound or endocytosed conjugates, rendering them into a sustained release dosage form.展开更多
基金funded by the National Science Center in Poland,Preludium grant number 2019/35/N/NZ6/02973.
文摘Introduction:Butyrophilins(BTNs)belong to the immunoglobulin superfamily;they play crucial roles in immune regulation,especially inγδ T cell activation.While their expression has been studied in solid tumours,their involvement in hematologic malignancies remains poorly understood.Objectives:We hypothesised that BTNs are dysregulated in chronic lymphocytic leukaemia(CLL),contributing toγδT cell dysfunction and potentially influencing disease progression.Methods:In this study,we analyzed publicly available microarray and RNA-seq datasets to investigate the expression patterns of BTN genes in CLL.Results:Our findings reveal significant dysregulation of BTN gene expression in CLL,with BTN2A1,BTN3A1,BTN3A2,and BTN3A3 being markedly downregulated in peripheral blood mononuclear cells(PBMCs)and bone marrow samples from CLL patients compared to healthy volunteers,while BTN1A1 was upregulated.Furthermore,BTN2A2 was selectively downregulated in neoplastic B cells,whereas BTN3A1 was upregulated in T cells from CLL patients compared to healthy volunteers.Notably,lower BTN expression was associated with an unmutated IGVH status and male sex.Kaplan-Meier survival analysis demonstrated that higher expression of BTN2A1,BTN3A1,BTN3A2,and BTN3A3 correlated with a significantly longer overall survival.Conclusions:Given the established role of BTN2A1 and BTN3A1 in the phosphoantigen-mediated activation of Vδ2γδ T cells,their downregulation may contribute toγδ T cell dysfunction in CLL.These results highlight the potential prognostic value of BTN gene expression in CLL and underscore the need for further studies exploring its mechanistic role in disease progression and immune evasion.
文摘BACKGROUND Hepatic manifestations in chronic lymphocytic leukemia(CLL)are common:Elevation of liver enzymes frequently occurs,and differential diagnosis is often challenging.Liver infiltration by leukemic cells,primary and secondary hepatic malignancies,drug-induced hepatotoxicity,immunological disorders,and infections have been reported.Nevertheless,syncytial giant cell hepatitis(GCH)as a manifestation of autoimmune hepatitis in patients with CLL is an extremely rare condition,currently reported only in anecdotal cases.CASE SUMMARY Here,we report the case of a 62-year-old Caucasian woman affected by CLL,who developed GCH with peculiar histopathological features.The patient was evaluated for abnormal liver test results.Liver histology revealed significant inflammatory lymphomononuclear infiltrates with a plasma cell component,widespread syncytial changes in the hepatocytes with gigantocellular features,hepatocyte rosettes,and the typical feature of emperipolesis,consistent with a diagnosis of GCH.The patient was treated with corticosteroids and mycophenolate mofetil,resulting in a complete biochemical response.CONCLUSION Early histological diagnosis of GCH is crucial in patients with CLL,with mycophenolate mofetil representing a promising treatment option.
文摘BACKGROUND Although previous findings indicated that pathological assessment of tumor budding(TB),desmoplastic reaction(DR),and tumor-infiltrating lymphocytes(TILs)may play a role in determining tumor behavior in many malignancies,the relationship between TB,DR,and TILs in patients with pancreatic ductal adenocarcinoma(PDAC)is still unknown.AIM To evaluate relationships of TB,DR,and TILs with histopathological parameters and determine their prognostic value in patients with PDAC.METHODS The study cohort comprised 100 patients diagnosed with PDAC.Peritumoral budding(PTB)and intratumoral budding(ITB)were assessed according to the International Tumor Budding Consensus Conference guidelines.DR was classified based on stromal maturation.TILs were evaluated semiquantitatively with a 5%cutoff.Additionally,cases were categorized into two groups according to lymphocyte density:No/Low lymphocytes and medium/high lymphocytes.RESULTS A significant correlation was observed between ITB and PTB(r=0.890).Higher PTB was associated with fewer TILs and immature stroma(P<0.001).PTB and TILs were significantly related to tumor dimension,lymphovascular invasion,lymph node metastasis(LNM),and stage(P<0.005).ITB was also associated with the presence of lymph node involvement.The results of the univariate analysis revealed a significant correlation between poor survival rates and the presence of lymphovascular invasion,LNM,PTB,ITB,and TILs according to scoring(P<0.001).The multivariate analysis revealed LNM,PTB,ITB,and TILs according to scoring as independent prognostic factors.CONCLUSION TB assessment stratified patients with PDAC.PTB-ITB correlation showed diagnostic relevance of ITB in biopsy specimens.The prognostic significance of DR and interplay with TIL subsets warrant further investigation.
文摘Pancreatic ductal adenocarcinoma(PDAC)is the most prevalent type of pan-creatic neoplasm.It is a highly aggressive lethal malignancy related to its delayed in diagnosis and limited response to treatments.The incidence and mortality of pancreatic cancer have been increasing over the years.Tumor budding is a proven independent,adverse prognostic factor in PDAC.It is helpful for improvement of prognosis in PDAC in early and precise diagnostic modalities.Tumor budding should be conveyed in pathology reports and taken into account by future onco-logic staging systems.
文摘AIM： TO investigate colonic endocrine cells in lympho- cytic colitis （LC） patients. METHODS： Fifty-seven patients with LC were in- cluded. These patients were 41 females and 16 males, with an average age of 49 years （range 19-84 years）. Twenty-seven subjects that underwent colonoscopy with biopsies were used as controls. These subjects underwent colonoscopy because of gastrointestinal bleeding or health worries, where the source of bleed- ing was identified as haemorrhoids or angiodysplasia. They were 19 females and 8 males with an average age of 49 years （range 18-67 years）. Biopsies from the right and left colon were obtained from both patients and controls during colonoscopy. Biopsies were fixed in 4% buffered paraformaldehyde, embedded in paraffin and cut into 5 μm-thick sections. The sections immunostained by the avidin-biotin-complex method for se- rotonin, peptide YY （PYY）, pancreatic polypeptide （PP） enteroglucagon and somatostatin cells. The cell densi- ties were quantified by computerised image analysis using Olympus software. RESULTS： The colon of both the patient and the control subjects were macroscopically normal. Histo- pathological examination of colon biopsies from con- trols revealed normal histology. All patients fulfilled the diagnosis criteria required for of LC： an increase in intraepithelial lymphocytes （〉 20 lymphocytes/100 epithelial cells） and surface epithelial damage with increased lamina propria plasma cells and absent or minimal crypt architectural distribution. In the colon of both patients and control subjects, serotonin-, PYY-, PP-, enteroglucagon- and somatostatin-immunoreac- tive cells were primarily located in the upper part of the crypts of Lieberk0hn. These cells were basket- or flask-shaped. There was no statistically significant dif- ference between the right and left colon in controls with regards to the densities of serotonin- and PYY- immunoreactive cells （P = 0.9 and 0.1, respectively）. Serotonin cell density in the right colon in controls was 28.9 ± 1.8 and in LC patients 41.6±2.6 （P = 0.008）. In the left colon, the corresponding figures were 28.5± 1.9 and 42.4± 2.9, respectively （P = 0.009）. PYY cell density in the right colon of the controls was 10.1 ± 1 and of LC patients 41 ± 4 （P = 0.00006）. In the left colon, PYY cell density in controls was 6.6± 1.2 and in LC patients 53.3 ± 4.6 （P = 0.00007）. CONCLUSION： The change in serotonin cells could be caused by an interaction between immune cells and serotonin cells, and that of PYY density might be sec- ondary.
文摘Chronic lymphocytic leukemia(CLL) is the most common leukemia in the western world. Despite significantadvances in therapy over the last decade CLL remains incurable. Current front-line therapy often consists of chemoimmunotherapy-based regimens, most commonly the fludarabine, cyclophosphamide plus rituximab combination, but rates of relapse and refractory disease are high among these patients. Several key signaling pathways are now known to mediate the survival and proliferation of CLL cells in vivo, the most notable of which are the pathways mediated by the B-cell receptor(BCR) and cytokine receptors. A better understanding of the pathogenesis of the disease, the underlying biology of the CLL-cell and the roles of the tumour microenvironment has provided the rationale for trials of a range of novel, more targeted therapeutic agents. In particular, clinical trials of ibrutinib and idelalisib, which target the Brutons tyrosine kinase and the delta isoform of phosphoinositol-3 kinase components of the BCR signaling pathway respectively, have shown extremely promising results. Here we review the current literature on the key signaling pathways and interactions of CLL cells that mediate the survival and proliferation of the leukemic cells. For each we describe the results of the recent clinical trials and in vitro studies of novel therapeutic agents.
基金supported by grants from the National Nature Science Foundation of China (No. 81200395, 81370632)the National Science and Technology supporting Program (No. 2014BAI09B12)+1 种基金the Fundamental Application and Advanced Technology Research Program of Tianjin (No. 15JCYBJC27900)the National Public Health Grand Research Foundation (No. 201202017)
文摘Objective： This study aims to evaluate the natural history of patients with chronic lymphocytic leukemia （CLL） and a 17p deletion （17p-） and identify the predictive factors within this subgroup. Methods： The sample of patients with CLL were analyzed by fluorescence in situ hybridization for deletions in chromosome bands 1 lq22, 13q14 and 17p13; trisomy of bands 12q13; and translocation involving band 14q32. The data from 456 patients with or without a 17p- were retrospectively collected and analyzed. Results： The overall response rate （ORR） in patients with a 17p- was 56.9%, and patients with a high percentage of 17p- （defined as more than 25% of cells harbouring a 17p-） had a lower ORR. The median overall survival （OS） in patients with a 17p- was 78.0 months, which was significantly shorter than the OS in patients without this genetic abnormality （median 162.0 months, P〈0.001）. Within the subgroup with a 17p-, the progression-free survival was significantly shorter in patients at Binet stage B-C and patients with elevated lactate dehydrogenase （LDH）, B symptoms, unmutated IGHVand a high percentage of 17p-. Conclusions： These results indicated that patients with a 17p- CLL have a variable prognosis that might be predicted using simple clinical and laboratory characteristics.
文摘Lymphocytic esophagitis (LE) is a clinicopathologic entity first described by Rubio et al in 2006. It is defined as peripapillary intraepithelial lymphocytosis with spongiosis and few or no granulocytes on esophageal biopsy. This definition is not widely accepted and the number of lymphocytes needed to make the diagnosis varied in different studies. Multiple studies have described potential clinical associations and risk factors for LE, such as old age, female gender and smoking history. This entity was reported in inflammatory bowel disease in the pediatric population but not in adults. Other associations include gastroesophageal reflux disease and primary esophageal motility disorders. The most common symptom is dysphagia, with a normal appearing esophagus on endoscopy, though esophageal rings, webs, nodularities, furrows and strictures have been described. Multiple treatment modalities have been used such as proton pump inhibitors and topical steroids. Esophageal dilation seems to be therapeutic when dysphagia is present along with esophageal narrowing secondary to webs, rings or strictures. The natural history of the disease remains unclear and needs to be better delineated. Overall, lymphocytic esophagitis seems to have a chronic and benign course, except for two cases of esophageal perforation in the literature, thought to be secondary to this entity.
文摘AIM： To find out the role of bacteria as a possible etiological factor in lymphocytic colitis. METHODS： Twenty patients with histopathological diagnosis of lymphocytic colitis and 10 normal controls were included in this study. Colonoscopic biopsies were obtained from three sites （hepatic and splenic flexures and rectosigmoid region）. Each biopsy was divided into two parts. A fresh part was incubated on special cultures for bacterial growth. The other part was used for the preparation of histologic tissue sections that were examined for the presence of bacteria with the help of Giemsa stain. RESULTS： Culture of tissue biopsies revealed bacterial growth in 18 out of 20 patients with lymphocytic colitis mostly Escherichia coil （14/18）, which was found in all rectosigmoid specimens （14/14）, but only in 8/14 and 6/14 of splenic and hepatic flexure specimens respectively. In two of these cases, E coli was associated with proteus. Proteus was found only in one case, Klebsiella in two cases, and Staphylococcus aureus in one case. In the control group, only 2 out of 10 controls showed the growth of E coli in their biopsy cultures. Histopathology showed rod-shaped bacilli in the tissue sections of 12 out of 14 cases with positive E coli in their specimen＇s culture. None of the controls showed these bacteria in histopathological sections. CONCLUSION： This preliminary study reports an association between E coli and lymphocytic colitis, based on histological and culture observations. Serotyping and molecular studies are in process to assess the role of E coli in the pathogenesis of lymphocytic colitis.
基金grants from the National Natural Science Foundation of China(No.81970146)National Science Foundation of China International Cooperation and Exchange Program(No.81720108002)+1 种基金National Science and Technology Major Project(No.2018ZX09734007)Six Talent Peaks Project in Jiangsu Province,2019(No.WSN-001).
文摘Chemoimmunotherapy(CIT)is defined as standard first line treatment for chronic lymphocytic leukemia(CLL)patients while patients with unfavorable biological characteristics such as unmutated immunoglobulin heavy chain(UM-IGHV)and TP53 aberration failed to benefit from it.The emergency of the small molecular targeted agents including Bruton’s tyrosine kinase(BTK)inhibitor(BTKi)leads to a brand-new era,from a CIT to a chemo-free era in CLL.However,the treatment of target agents is not enough to attain a deep remission and high rate of complete remission(CR),especially in patients with high risks.The long duration brought about problems,such as cost,drug resistance and toxicity.To benefit CLL in progression free survival(PFS)and long-term remission,exploration of time-limited therapies,mainly with BTKi plus CIT and BCL2i based combination therapy has become a mainstream in clinical trials.The time-limited combination therapy shed light on the promising potentiality to attain sustainable deep remission and partly overcame the risk factors,although long term follow-up is required to consolidate the conclusion.In this review,we intend to introduce key results of clinical trials with combination therapy,discuss the achievements and limitations and put forward future direction for clinical trial design in this field.
文摘BACKGROUND The concurrence of acute myeloid leukemia(AML)and chronic lymphocytic leukemia(CLL)is rare.Previous reports of such cases have focused mainly on clinical diagnosis and characteristics,so the mechanism remains unclear,and therapy options have been poorly explored.CASE SUMMARY Here,we report two cases of synchronous AML and CLL.Flow cytometry revealed two distinct abnormal cell populations(myeloblasts and lymphoid cells)according to scatter characteristics.CD5-positive B cell lymphoma with myeloid leukemia invasion was observed on lymph node biopsy.Chemotherapy regimens indicated for both AML and CLL were used in our patients,and our patients achieved complete response after chemotherapy.Next-generation sequencing of 88 genes was performed.CONCLUSION We conclude that early mutation and dysregulation at the hematopoietic stem cell stage and the accumulation of multiple rearrangements may cause the concurrence of CLL and AML.The treatment of infection and combination therapy aimed at the CLL component are significant in the management of patients with concurrent CLL and AML.
文摘We describe a patient with concomitant B-cell chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). CLL- and MM-cell were separated by preparative flourescence-activated cell sorting (FACS). DNA sequence analysis of the complementarity-determinining region III (CDR III) of the immunoglobulin heavy chain genes showed identical gene rearrangements in the CLL- and the MM-cell population. Our findings prove a common clonal tumor origin of both B-cell diseases in this patient.
文摘Using Southern blot, Northern blot and Quick blot methods, we examined the rearrangement and expression of TCR βgene in four early differentiation stage cell lines from human hemopoietic system, namely HL-60, Jurkat, Daudi and Raji cells as well as lymphocytes from 17 acute lymphocytic leukemia （ALL） patients. The results showed. Ⅰ) Rearrangement of TCR βgene was seen in Jurkat cells. A germline pattern was observed in HL-60, Daudi and Raji cells. 2) Eight of 9 patients with T-ALL had cells with rearranged TCR βgene. But two of 3 patients with B-ALL and three of 5 patients with nonT, nonB-ALL also had cells with rearranged TCR βgene. 3) A 1.3 kb full-length transcript and a 1.0 kb truncated transcript were detected in Jurkat cells by probing with <sup>32</sup>P-TCR βcDNA. But some leukemic B cells also expressed an incompleted transcript. 4) TCR βmRNA was detected in six of 8 patients with T-ALL, four of 5 patients with nonT, nonB-ALL and one of 3 patients with B-ALL. But the level of expression was quite differ ent. The dual-rearrangement and the abnormal expression may give us a new clue for researching leukemogenesis.
基金Supported by the Nature Science Foundation of Jilin Province(No.2018010113JC).
文摘BACKGROUND Lymphocytic hypophysitis(LYH)is an important condition to consider in the differential diagnosis of patients with a pituitary mass.The main clinical manifestations of LYH include headache,symptoms related to sellar compression,hypopituitarism,diabetes insipidus and hyperprolactinemia.Headache,which is a frequent complaint of patients with LYH,is thought to be related to the occupying effect of the pituitary mass and is rapidly resolved with a good outcome after timely and adequate glucocorticoid treatment or surgery.CASE SUMMARY Here,we report a patient with LYH whose initial symptom was headache and whose pituitary function assessment showed the presence of secondary hypoadrenalism,central hypothyroidism and hypogonadotropic hypogonadism.Pituitary magnetic resonance imaging showed symmetrical enlargement of the pituitary gland with suprasellar extension in a dumbbell shape with significant homogeneous enhancement after gadolinium enhancement.The size of the gland was approximately 17.7 mm×14.3 mm×13.8 mm.The pituitary stalk was thickened without deviation,and there was an elevation of the optimal crossing.The lesion grew bilaterally toward the cavernous sinuses,and the parasternal dural caudal sign was visible.The patient presented with repeatedly worsening and prolonged headaches three times even though the hypopituitarism had fully resolved after glucocorticoid treatment during this course.CONCLUSION This rare headache regression suggests that patients with chronic headaches should also be alerted to the possibility of LYH.
文摘Determination of minimal residual disease (MRD) remains crucial for the follow-up after therapy in chronic lymphocytic leukemia (CLL) patients. Chimerism was assessed by short tandem repeat (STR)-PCR and single nucleotide polymorphisms (SNP)-PCR, and MRD by a multicolor flow cytometric approach in 12 consecutive patients with CLL after they received allogeneic stem cell transplantation (SCT). Overall, 11 patients achieved MRD flow negativity [10 had full donor chimerism (FDC) and one had mixed chimerism (MC)]. Only one patient remained with MRD flow positivity and displayed MC. Fifty-six samples were concomitantly studied by both chimerism and MRD flow. A significant correlation was observed between MRD flow data and chimerism in both PB and BM by using a mixed effect linear regression (p < 0.001). Flow cytometry approach of MRD can be easily combined with chimerism during the follow-up post-allogeneic SCT. Both techniques appeared complementary for guiding post-transplant immunomodulation.
文摘Papular mycosis fungoides(MF) is a rare presentation of MF. Six illustrative cases of papular MF were retrospectively reviewed. Five of the cases studied by immunohistochemistry had variable numbers(range: 1%-20%) of CD30+ cells in the dermal infiltrate, a finding that is characteristic of lymphomatoid papulosis but may occasionally occur in typical early MF. Although none of our papular MF patients had progressive disease, lesions with relatively high numbers of CD30+ cells in 3 patients did not respond well to skin-directed treatments used for MF. Interestingly, these patients had evidence of coexisting clonal B cell populations in the blood(one with clonal B cell lymphocytosis and two with B-cell chronic lymphocytic leukemia). We conclude that:(1) papular MF may contain CD30+ cells, thereby causing confusion with lymphomatoid papulosis; and(2) papular MF, like more typical MF, may be associated with clonal B-cell proliferations including chronic lymphocytic leukemia.
文摘Previous studies have shown that the bcl-2protooncogene encodes a mitochondrial protein thatpromotes cell survival by blocking programmed celldeath. High levels of bcl-2 expression were found inmurine myeloid leukemic cell lines resistant to apoptosisinduced by variety of agents. In addition artificialelevation of bcl-2 expression in a human pre-B leukemiccell line resulted in enhanced resistance to chemo-therapcutic drugs. We reported here on the effect ofbcl-2 antisense phosphorothiate
文摘Curcumin is a widely researched natural product and is known to possess anticarcinogenic properties.Chronic lymphocytic leukemia is a type of leukemia that principally affects patients with age higher than 60 years.Since the toxicity of conventional drugs exceeds the benefits of treating this leukemia type,patients are treated only in the advanced symptomatic stages.The current article reviews curcumin,its general actions and targets in cancer,and specifically that of it in chronic lymphocytic leukemia.
文摘AIM To evaluate the potential association between mild duodenal damage and microscopic colitis(MC).METHODS We retrospectively included 105 consecutive patients with type I Marsh-Oberhuber duodenal damage and negativity for immunoglobulin A anti-endomysium and anti-tissue transglutaminase.The following parameters were analyzed:Sex,age at execution of esophagogastroduodenoscopy,duodenal damage,and number of intraepithelial lymphocytes at biopsies,prevalenceof Helicobacter pylori infection,age at execution of colonoscopy,macroscopic and microscopic features of colonoscopy,family history of gastrointestinal and autoimmune diseases,smoking habits,biochemical parameters of inflammation and autoimmunity,use of proton pump inhibitors or nonsteroidal anti-inflammatory drugs,adverse reactions to drugs or foods,pathologies known to be associated with celiac disease or MC,living on a gluten-free diet or on a gluten-low diet for at least 1 mo.RESULTS Colonoscopy was performed in 59 patients,but only in 48 of them biopsies were taken in the entire colon.Considering the latter cohort,the diagnosis of MC was met in 25(52.1%) patients while in 18 patients other pathologic findings were reported:13(27%) cases of nonspecific inflammatory bowel disease,2(4.2%) cases of Crohn's disease,2(4.2%) cases of eosinophilic gastroenteritis,and 1(2.1%) case of autoimmune enteritis.Five(10.4%) patients had a normal colonoscopic result.Matching the groups by age,and considering only patients who underwent colonoscopy(42.7 ± 15.5 years) vs those who did not undergo colonoscopy(36.9 ± 10.6 years),a statistical difference was found(P = 0.039).Focusing on symptoms,diarrhea was statistically more prevalent in MC group than in patients who did not undergo colonoscopy(P = 0.03).CONCLUSION Mild duodenal damage is associated with MC in more than half of the cases.This association supports the hypothesis of a link between these two entities.
文摘Objective: To analysis the uptake of free MTX and MTX conjugated to tumor specific monoclonal antibody by target and nontarget cells. Methods: The folate antagonist methotrexate (MTX) was conjugated to two monoclonal antibodies (Mab) directed against human chronic lymphocytic leukemia (CLL), Dal B01 and Dal B02, by an active ester method. Both conjugates were more cytotoxic toward the target tumor cell line D101 than to the nontarget cell line MOLT3, and Dal B02MTX conjugate was more inhibitory to D101 cells than free MTX in a 6 h pulse exposure assay. Results: Drug uptake studies revealed that D101 cells took up much more Dal B01 and Dal B02conjugated MTX than free MTX. The amounts of drug taken up by D101 cells incubated with Dal B01 and Dal B02conjugated MTX were always 3 to 5fold higher than that taken up by MOLT3 cells, although the latter took up more drug when incubated with free MTX. Furthermore, tumor cells incubated with Dal B01 or Dal B02conjugated MTX retained much larger amounts of drug for a prolonged period of time than those incubated with free MTX. Conclusion: The enhanced specific cytotoxicity of Dal B01 and Dal B02MTX conjugates toward target tumor cells is therefore likely due to (I) delivery of larger amounts of MTX to target cells when the drug is conjugated to Mab; (ii) longer retention of Mabconjugated MTX by target cells; and (iii) slow, prolonged release of MTX from the surfacebound or endocytosed conjugates, rendering them into a sustained release dosage form.
