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Histologic Evidence (histologic + evidence)
Selected AbstractsRelationship of clinical and pathologic response to neoadjuvant chemotherapy and outcome of locally advanced breast cancer,JOURNAL OF SURGICAL ONCOLOGY, Issue 1 2002Csaba Gajdos MD Abstract Background and Objectives Neoadjuvant chemotherapy in locally advanced breast cancers produces histologically evaluable changes and frequently reduces the size of the primary tumor. Local clinical response to neoadjuvant chemotherapy may correlate with response of distant metastases. Therefore, clinical or pathological factors, which predict or assess response to treatment, may predict outcome after consideration for initial extent of disease. Methods To identify pretreatment characteristics of locally advanced breast cancers which predict clinical and pathologic response to neoadjuvant chemotherapy as well as survival and to assess the utility of postoperative histologic changes, we retrospectively studied one hundred forty-four patients with locally advanced breast cancer treated with neoadjuvant chemotherapy between January 1975 and July 1996. Patients were identified through pathology records of the Mount Sinai Medical Center and via one of the author's clinical databases. Pathologic and clinical responses to neoadjuvant chemotherapy were correlated with survival. Stepwise logistic regression was used to identify variables most significantly related to clinical response and pathologic axillary lymph node involvement. Results Complete clinical response with no palpable tumor was noted in 7/86 patients (8%) and complete pathologic response was achieved in 18/138 patients (13%). Both clinical (P,=,0.038) and pathologic response (P,=,0.011) were related to tumor size at the time of diagnosis: smaller tumors were more likely to respond to chemotherapy than larger tumors. Histologic evidence of chemotherapeutic effect, i.e., cytoplasmic vacuolization, change in the number of mitoses and localized fibrosis in lymph nodes did not correlate with clinical or pathologically measured response. Clinical and pathologic response was not associated with age, histology, differentiation, or type of chemotherapy. No residual tumor was found in the axillary nodes of 27% (37) of the patients. Age and complete pathologic response were the only variables significantly related to pathologic nodal status. Eighty-four percent of the 61 patients under 50 years of age had nodal involvement compared to 65% of older patients (P,=,0.014). Fifty percent of complete pathologic responders had positive axillary lymph nodes compared to 76% of patients who did not have a complete pathologic response (P,=,0.020). Distant disease-free (P,=,0.039) and overall survival (P,=,0.035) were related to the number of involved axillary lymph nodes. After consideration for pathologic lymph node status, no other variable was significantly related to distant disease-free or overall survival in multivariate analysis. No variable was significantly related to local disease-free survival. Age, clinical tumor size, clinical lymph node status, clinical response, type of chemotherapy, histology, differentiation, chemotherapy effects on primary tumor and lymph nodes, decline in the number of mitoses, and degree of fibrosis in nodes were not predictive of distant recurrence or overall survival. Conclusions This study of patients treated with neoadjuvant chemotherapy for locally advanced breast cancers found little evidence that measurable clinical or pathologic changes attributable to chemotherapy predicted survival. Axillary lymph node status, associated with young age, was the most important prognostic indicator in these patients. J. Surg. Oncol. 2002;80:4,11. © 2002 Wiley-Liss, Inc. [source] Treatment of Lentigo Maligna with Imiquimod before Staged ExcisionDERMATOLOGIC SURGERY, Issue 2 2008MURRAY A. COTTER MD BACKGROUND Imiquimod 5% cream has demonstrated effectiveness in the treatment of lentigo maligna (LM) in several small studies. None of the studies to date have included posttreatment surgical removal to confirm negative histologic margins. OBJECTIVE The aim of this retrospective analysis was to assess the efficacy of topical imiquimod in LM by circumferentially examining vertically oriented sections from a geometrically designed "picture frame" margin as well as bread-loafed sections of the central portion after staged excisions of imiquimod-treated lesions of LM. METHODS Forty patients with biopsy-confirmed LM were treated five times a week for 3 months with 5% imiquimod cream before staged excision. Tazarotene 0.1% gel was added when no clinical signs of erythema developed with imiquimod alone after 1 month (10 patients). After the course of topical therapy, patients were assessed for clinical and complete histologic clearance after staged excision. RESULTS A total of 33 of 40 patients had a complete clinical response as determined by the absence of remaining clinical lesion on physical examination. Upon histologic review, 30 of 40 patients had no evidence of LM whereas 10 of 40 harbored residual disease. One patient was found to have histologic evidence of invasion after completing the topical protocol. After a mean follow-up of 18 months (range, 12,34 months) and after complete surgical excision of the treatment site, none of the imiquimod-treated patients had evidence of recurrence. CONCLUSIONS Imiquimod appears to be an effective adjunctive treatment for LM but does not qualify as a replacement therapy for surgery. [source] Pentylenetetrazol-induced Recurrent Seizures in Rat Pups: Time Course on Spatial Learning and Long-term EffectsEPILEPSIA, Issue 6 2002Li-Tung Huang Summary: ,Purpose: Recurrent seizures in infants are associated with a high incidence of neurocognitive deficits. Animal models have suggested that the immature brain is less vulnerable to seizure-induced injury than is that in adult animals. We studied the effects of recurrent neonatal seizures on cognitive tasks performed when the animals were in adolescence and adulthood. Methods: Seizures were induced by intraperitoneal injection of pentylenetetrazol (PTZ) for 5 consecutive days, starting from postnatal day 10 (P10). At P35 and P60, rats were tested for spatial memory by using the Morris water maze task. In adulthood, motor performance was examined by the Rotarod test, and activity level was assessed by the open field test. Seizure threshold was examined by inhalant flurothyl. To assess presence or absence of spontaneous seizures, rats were video recorded for 4 h/day for 10 consecutive days for the detection of spontaneous seizures. Finally, brains were examined for histologic evidence of injury with cresyl violet stain and Timm staining in the supragranular zone and CA3 pyramidal cell layers of the hippocampus. Results: PTZ-treated rats showed significant spatial deficits in the Morris water maze at both P35 and P60. There were no differences in seizure threshold, motor balance, or activity level during the open field test. Spontaneous seizures were not recorded in any rat. The cresyl violet stain showed no cell loss in either the control or experimental rats. PTZ-treated rats exhibited more Timm staining in the CA3 subfield. However, the control and experimental rats showed similar Timm staining within the supragranular zone. Conclusions: Our findings indicate that recurrent PTZ-induced seizures result in long-term cognitive deficits and morphologic changes in the developing brain. Furthermore, these cognitive deficits could be detected during pubescence. [source] Benign metastasizing pleomorphic adenoma of the parotid gland: A clinicopathologic puzzleHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 12 2003Gino Marioni MD Abstract Background. Pleomorphic adenoma constitutes the most common benign parotid gland tumor. Local recurrence after surgical treatment (lateral or total parotidectomy) has been described in 1% to 5% of cases. Malignant degeneration has been reported in 2% to 9% of cases of pleomorphic adenoma of salivary gland origin. Metastasizing pleomorphic adenomas without histologic evidence of malignancy have rarely been reported. Metastatic lesions have been discovered in bone, lymph nodes, the lung, oral cavity, pharynx, skin, liver, retroperitoneum, kidney, calvarium, and central nervous system. To the best of our knowledge, we hereby report the first case of pleomorphic adenoma of the parotid gland metastasizing to the ipsilateral maxilla. Methods. We simultaneously examined apoptosis-related protein expression and markers of cell-proliferation activity in our case of benign pleomorphic adenoma metastasis and compared outcome with a control group of primary parotid pleomorphic adenomas. Results. Analysis of p53, Bcl-2, MIB1, CD 105, p27, and p21 expression did not reveal significant differences between metastasizing pleomorphic adenoma of the salivary gland and the control group of primary parotid pleomorphic adenomas. Conclusions. Clinical rather than pathologic evidence seems to justify inclusion of metastasizing salivary pleomorphic adenoma in the group of low-grade malignant salivary tumors. © 2003 Wiley Periodicals, Inc. Head and Neck 25: 000,000, 2003 [source] Decreased hepatic nitric oxide production contributes to the development of rat sinusoidal obstruction syndromeHEPATOLOGY, Issue 4 2003Laurie D. Deleve M.D., Ph.D. This study examined the role of decreased nitric oxide (NO) in the microcirculatory obstruction of hepatic sinusoidal obstruction syndrome (SOS). SOS was induced in rats with monocrotaline. Monocrotaline caused hepatic vein NO to decrease by 30% at 24 hours and by 70% at 72 hours; this decrease persisted throughout late SOS. NG -nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, exacerbated monocrotaline toxicity, whereas V-PYRRO/NO, a liver-selective NO donor prodrug, restored NO levels, preserved sinusoidal endothelial cell (SEC) integrity and sinusoidal perfusion as assessed by in vivo microscopy and electron microscopy, and prevented clinical and histologic evidence of SOS. NO production in vitro by SEC and Kupffer cells, the 2 major liver cell sources of NO, decreases largely in parallel with loss of cell viability after exposure to monocrotaline. Increased matrix metalloproteinase (MMP) activity increases early on in SOS and this increase in activity has been implicated in initiating SOS. Infusion of V-PYRRO-NO prevented the monocrotaline-induced increase in MMP-9. In conclusion, decreased hepatic NO production contributes to the development of SOS. Infusion of an NO donor preserves SEC integrity and prevents development of SOS. These findings show that a decrease in NO contributes to SOS by allowing up-regulation of MMP activity, loss of sinusoidal integrity, and subsequent disruption of sinusoidal perfusion. (Hepatology 2003;38:900,908). [source] Early identification of recipients with progressive histologic recurrence of hepatitis C after liver transplantationHEPATOLOGY, Issue 5 2000Raghavakaimal Sreekumar Approximately half of patients undergoing liver transplantation (LT) for hepatitis C virus (HCV) develop histologic evidence of recurrence within the first postoperative year. Early identification of recipients at risk for more severe recurrence of HCV may be useful in selecting patients for antiviral therapy. We determined whether recipients at greatest risk for more severe recurrence of HCV can be identified by pre- and/or early post-LT HCV-RNA levels in serum or tissue. Serum and tissue samples were prospectively collected pre-LT and at 7 days, 4 months, 1 year, and at 3 years posttransplantation from patients undergoing LT for HCV. Hepatitis activity index (HAI) and fibrosis stage (FS) were assessed in all liver biopsies. Forty-seven patients (32 men) were studied. Higher HCV-RNA levels at 4 months post-LT (,109 copies/mL, n = 29) were associated with higher HAI at 1 year and at 3 years post-LT. The HAI seen on protocol biopsies at 4 months correlated significantly with fibrosis stage (FS) at 1 year (r = .56, P , .001) and 3 years (r = .53, P = .002). Higher HCV-RNA levels at 7 days and 4 months post-LT were sensitive (66% and 84%, respectively) and specific (92% and 63%, respectively) in identifying recipients with an HAI greater than 3 at 3 years. Higher pre- and early post-LT HCV-RNA levels are associated with more severe recurrence of HCV. The correlation of early HAI with subsequent FS suggests that higher mean HAI will eventually translate into more advanced stages of fibrosis. Patients at risk for more severe post-LT recurrence of HCV can be identified by early posttransplant HCV-RNA levels. [source] Time Course of Esophageal Lesions After Catheter Ablation with Cryothermal and Radiofrequency Ablation: Implication for Atrio-Esophageal Fistula Formation After Catheter Ablation for Atrial FibrillationJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 6 2007KENNETH LAUREN RIPLEY M.S.E.E. Background: Atrio-esophageal fistulas have been described as a consequence of radiofrequency (RF) ablation for the treatment of atrial fibrillation (AF). However, whether cryoablation can avoid this potential fatal complication remains unclear. Methods and Results: We studied the effects of direct application of RF and cryoablation on the cervical esophagus in 16 calves. Cryoablation was performed with a 6.5-mm catheter probe using a single 5-minute freeze at <,80°C, and RF ablation was delivered with an 8-mm catheter electrode at 50 W and 50°C for 45,60 seconds. Histopathologic assessments were performed at 1, 4, 7, and 14 day(s) after completion of the ablation protocol: four animals were examined each day. A total of 85 direct esophageal ablations were performed: 41 with RF and 44 with cryoablation. There were no significant differences in lesion width, depth, or volume between cryoablation and RF ablation at Day 1, 4, and 14 after the procedure (P > 0.05). However, lesion width and volume were significantly larger with RF than with cryoablation at Day 7. Although acute (Day 1) and chronic (Day 14) RF and cryoablation lesions were of comparable size, histologic evidence of partial- to full-wall esophageal lesion ulceration was observed in 0 of 44 (0%) lesions with cryoablation, compared with 9 of 41 (22%) lesions with RF ablation (P = 0.0025). Conclusions: Direct application of cryoablation and RF ablation created similar acute and chronic lesion dimensions on the esophagus. However, cryoablation was associated with a significantly lower risk of esophageal ulceration, compared with RF ablation. [source] Value of ADAMTS13 activity and inhibitor in the postmortem diagnosis of thrombotic thrombocytopenic purpuraJOURNAL OF CLINICAL APHERESIS, Issue 3 2009Denis M. Dwyre Abstract Background and Objectives: Thrombotic thrombocytopenic purpura (TTP) is a clinical diagnosis that can be difficult to establish in severely ill patients. We report a case of fulminant TTP in a woman who died before receiving plasma exchange. An autopsy plasma sample was analyzed for ADAMTS13 activity and inhibitor for correlation with the diagnosis of TTP. Recognizing that hemolysis in postmortem blood samples could interfere with ADAMTS13 activity, plasma samples from four additional decedents not suspected of having TTP were analyzed and correlated with their autopsy results. The purpose of this study was to assess whether testing postmortem samples for ADAMTS13 is useful in the postmortem diagnosis of TTP. Material and Methods: Plasma samples from the index case and four non-TTP decedents were analyzed for ADAMTS13 activity, ADAMTS13 inhibitor levels, and plasma free hemoglobin (PFH). Autopsy tissues were evaluated for evidence of platelet microthrombi in all five cases. Results: The ADAMTS13 activity level in the index patient was <4%, and the inhibitor level was 1.0 inhibitor unit. Microthrombi were prominent in the heart, kidneys, pancreas, and adrenal glands, consistent with the clinical diagnosis of TTP. ADAMTS13 activity levels in the four non-TTP decedents ranged from 4 to 82% (3/4 , 26%), and inhibitor was present in two of the four samples. Postmortem PFH levels in the four non-TTP decedents ranged from 64 to 3,917 mg/dL. No microthrombi were observed. Conclusion: Low postmortem ADAMTS13 activity and evidence of inhibitor can occur in decedents without clinical or histologic evidence of TTP. Postmortem ADAMTS13 activity levels may not be valid in establishing a diagnosis of TTP, and high inhibitor levels in this setting may be related to elevated PFH. Caution must be used in the interpretation of ADAMTS13 testing in the presence of hemolysis. J. Clin. Apheresis 2009. © 2009 Wiley-Liss, Inc. [source] Endoscopic ultrasound guided fine needle aspiration of solid pancreatic lesions: Performance and outcomesJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 1 2009Leon Fisher Abstract Background and Aim:, We report our single-centre experience with endoscopic ultrasound guided fine needle aspiration (EUS-FNA) of solid pancreatic lesions with regard to clinical utility, diagnostic accuracy and safety. Methods:, We prospectively reviewed data on 100 consecutive EUS-FNA procedures performed in 93 patients (54 men, mean age 60.6 ± 12.9 years) for evaluation of solid pancreatic lesions. Final diagnosis was based on a composite standard: histologic evidence at surgery, or non-equivocal malignant cytology on FNA and follow-up. The operating characteristics of EUS-FNA were determined. Results:, The location of the lesions was pancreatic head in 73% of cases, the body in 20% and the tail in 7%. Mean lesion size was 35.1 ± 12.9 mm. The final diagnosis revealed malignancy in 87 cases, including adenocarcinomas (80.5%), neuroendocrine tumours (11.5%), lymphomas (3.4%) and other types (4.6%). The FNA findings were: 82% interpreted as malignant cytology, 1% as suspicious for neoplasia, 1% as atypical, 7% as benign process and 9% as non-diagnostic. No false-positive results were observed. There was a false-negative rate of 5%. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 94.3%, 100%, 100%, 72.2% and 95%, respectively. In 23 (88.5%) of 26 aspirated lymph nodes malignancy was found. Minor complications occurred in two patients. Conclusions:, Our experience confirms that EUS-FNA in patients with suspected solid pancreatic lesions is safe and has a high diagnostic accuracy. This technique should be considered the preferred test when a cytological diagnosis of a pancreatic mass lesion is required. [source] Patients with stable uncomplicated cirrhosis have normal neutrophil functionJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 11 2000Richard Kirsch Abstract Background: Neutrophil function has been reported to be abnormal in patients with cirrhosis. In order to evaluate the relative contribution of hepatocellular dysfunction and portalsystemic shunting of blood to these abnormalities, neutrophil function was studied in 18 patients with cirrhosis and portal hypertension. Nine patients, with extrahepatic portal hypertension (EPH) caused by portal vein thrombosis, who had no clinical, biochemical or histologic evidence of liver disease were also studied. Methods: Superoxide generation, phagocytosis, degranulation, leukotriene B4 release, candidacidal activity and quantitative and qualitative expression of the cell surface adhesive marker CD11b/CD18 were measured in these patients as well as in age- and gender-matched controls. Results: Patients with cirrhosis were found to have a small but statistically significant decrease in the expression of the CD18 component of MAC1 in N -formyl-methionyl-leucyl-phenylalanine-stimulated neutrophils (P = 0.04). No significant differences were found between either of the two patient groups and the control group for any of the other parameters of neutrophil function tested. Conclusions: These were unexpected findings in the light of data published elsewhere, which indicate impaired neutrophil function in patients with cirrhosis. The study suggests that patients with stable, uncomplicated cirrhosis and patients with EPH have normal neutrophil function. [source] Thyrotropin-Releasing Hormone Stimulation Test to Assess Thyroid Function in Severely Sick CatsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 2 2001Kamil Tomsa Basal serum thyroxine (T4) concentration and the thyrotropin-releasing hormone (TRH) stimulation test were used to assess thyroid function in 36 critically ill cats examined between July 1996 and October 1998. Of the 36 cats, hyperthyroidism (as underlying or complicating disease) was suspected in 22 based on clinical signs, palpable thyroid nodules, and abnormal thyroid gland histology (study group). Hyperthyroidism was not suspected in the remaining 14 cats, which served as the control group. Based on serum T4 concentrations, suppression of thyroid function was documented in 14 (64%) cats of the study group and in 10 (71%) cats of the control group. The TRH stimulation test revealed an increase in serum T4 of less than 50% of the baseline concentration in 18 (82%) cats of the study group, and in 6 (43%) cats of the control group. In conclusion, based on the results of serum T4 determinations and the TRH stimulation tests, it was not possible to differentiate between cats with clinical and histologic evidence of thyroid dysfunction (hyperthyroidism) and cats with severe nonthyroidal illnesses. [source] Graft rejection occurring in post,liver transplant patients receiving cytotoxic chemotherapy: A case seriesLIVER TRANSPLANTATION, Issue 6 2009Hui-Hui Tan Liver transplant recipients are known to be at increased risk for the development of de novo neoplasms or the recurrence of preexisting malignancies, and this is possibly related to the use of immunosuppressive medication. Little is known about the effects of cytotoxic chemotherapy on graft function after transplantation. A retrospective chart and pathology database review was undertaken to identify post,liver transplant patients developing rejection during chemotherapy. All liver biopsies were reviewed by a hepatopathologist. Three patients were identified. All patients were diagnosed with cancer within 7 years of liver transplantation; two-thirds died soon after the diagnosis of malignancy. Rejection occurred soon after chemotherapy was started. All patients were receiving prednisone and tacrolimus (trough levels: 2.1-4.8 ng/mL). One patient developed plasma cell hepatitis (de novo autoimmune hepatitis). There was no histologic evidence of hepatotoxicity due to the chemotherapeutic agents. Cytotoxic chemotherapy should be used in liver transplant recipients with caution, and immunosuppressant doses should be maintained at therapeutic levels, as patients may be at risk for allograft rejection. Treatment of rejection or plasma cell hepatitis in this setting should be undertaken in a timely and aggressive fashion to prevent chronic ductopenic rejection. Liver Transpl 15:634,639, 2009. © 2009 AASLD. [source] Effects of interferon treatment on liver histology and allograft rejection in patients with recurrent hepatitis C following liver transplantationLIVER TRANSPLANTATION, Issue 7 2004R. Todd Stravitz Recurrent hepatitis C after liver transplantation remains a significant cause of graft loss and retransplantation. Although treatment of recurrent hepatitis C with interferon-based regimens has become widely accepted as safe and can lead to sustained virologic clearance of hepatitis C virus (HCV) RNA, long-term histologic improvement and the risk of precipitating graft rejection remain controversial. The present study is a retrospective evaluation of the clinical and histological consequences of treating recurrent hepatitis C with interferon-based therapy in a selected group of liver transplant recipients. Twenty-three liver transplant recipients with recurrent hepatitis C and histologic evidence of progressive fibrosis completed at least 6 months of interferon, 83% of whom received pegylated-interferon ,-2b; only 4 tolerated ribavirin. Overall, 11 patients (48%) had undetectable HCV RNA at the end of 6 months of treatment. Of these patients, 3 remained HCV RNA,negative on maintenance interferon monotherapy for 33 months, and the other 8 (35%) completed treatment and remained HCV RNA,undetectable 24 weeks after discontinuation of interferon. Overall necroinflammatory activity in liver biopsies obtained 2 years after HCV RNA became undetectable decreased significantly (7.73 ± 2.37 vs. 5.64 ± 2.94 units before and after treatment, respectively; P = .016). However, 5 of these 11 patients had no histologic improvement in follow-up liver histology. Liver biopsies in the 12 nonresponders demonstrated disease progression. Of the 23 patients treated with interferon, 8 (35%) had evidence of acute or chronic rejection on posttreatment liver biopsy, most of whom had no previous history of rejection (P < .01 for comparison of pretreatment and posttreatment prevalence of histologic rejection), and 2 experienced graft loss from chronic rejection, requiring retransplantation. In conclusion, interferon treatment of recurrent hepatitis C does not consistently improve histologic disease after virologic response, and it may increase the risk of allograft rejection. (Liver Transpl 2004;10:850,858.) [source] Alpha-fetoprotein producing uterine corpus carcinoma: A hepatoid adenocarcinoma of the endometriumPATHOLOGY INTERNATIONAL, Issue 10 2000Hiroshi Toyoda A case of alpha-fetoprotein (AFP) producing endometrial carcinoma in a 60-year-old Japanese woman is presented. The patient complained of abnormal vaginal bleeding of 10 days' duration. On admission a uterine corpus mass and high serum AFP concentration (31950 ng/mL) was noted. There was no tumorous lesion in any other organ radiographically and endoscopically. Histologically, the biopsy specimen taken from the uterine mass showed a poorly differentiated endometrial carcinoma and a radical hysterectomy was subsequently performed. The postoperative serum AFP value transiently decreased with chemotherapy, however, lung metastases were found and the patient died 12 months following surgery. The resected uterus had a necrotic tumor, 6 × 5 × 4 cm in size, filling the endometrial cavity, characterized by exophytic growth with infiltration in the myometrium. Histologically, the tumor was composed of the main medullary carcinoma area with microcysts and admixed small areas of well-differentiated endometrioid adenocarcinoma, accompanied by a smooth transition with one another. In both the areas, the tumor cells had immunoreactive AFP, alpha-1-antitripsin, albumin, transferrin, carcinoembryonic antigen, CA19-9, and epithelial membrane antigen. There was no histologic evidence for a germ cell tumor. Based on these findings, this uterine corpus tumor was regarded as hepatoid variant of endometrial carcinoma. Although the histogenesis remains controversial, we assume the hypothesis that the tumor may arise in the endometrium per se in association with abnormal differentiation of muellerian duct elements. [source] C4d and C3d Staining in Biopsies of ABO- and HLA-Incompatible Renal Allografts: Correlation with Histologic FindingsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2006M. Haas Biopsies of ABO-incompatible and positive crossmatch (HLA-incompatible) renal allografts were retrospectively examined to compare results of C4d and C3d staining, and the correlation between such staining and histologic findings suggestive of antibody-mediated rejection (AMR). A total of 75 biopsies (55 protocol, 17 for graft dysfunction, 3 for other indications) of 24 ABO-incompatible grafts and 244 biopsies (103 protocol, 129 for graft dysfunction, 12 for other indications) of 66 HLA-incompatible grafts were examined; all were stained for C4d and ,40% for C3d. In ABO-incompatible grafts, 80% of protocol biopsies and 59% performed for graft dysfunction showed C4d staining in peritubular capillaries (PTC); this staining was not correlated with neutrophil margination in PTC. In HLA-incompatible grafts, PTC C4d was present in 26% of protocol biopsies and 60% of biopsies for graft dysfunction; 92% of biopsies with >1+ (0,4+ scale), diffuse PTC C4d had ,1+ margination and/or thrombotic microangiopathy (TMA), compared with 12% of C4d-negative biopsies. C3d was somewhat more predictive of margination than C4d in ABO-incompatible, but not HLA-incompatible, grafts. In summary, while PTC C4d deposition indicates probable AMR in biopsies of HLA-incompatible grafts, including protocol biopsies, there is no histologic evidence that C4d deposition is correlated with injury in most ABO-incompatible grafts. [source] BS13 THE EFFECT OF ANTIBIOTIC TREATMENT OF INFLAMMATORY BREAST DISEASE ASSOCIATED WITH THE ISOLATION OF LIPOPHILIC CORYNEBACTERIAANZ JOURNAL OF SURGERY, Issue 2007A. M. Skinner Granulomatous mastitis is a rare benign condition effecting women of reproductive age and is most commonly treated surgically. It is an inflammatory disease of the breast associated with the isolation of intracellular lipophilic corynebacteria and has a course of chronicity with recurrences. Purpose , Our aim was to observe the clinical response and subsequent course of women diagnosed with granulomatous mastitis and treated by a long course of lipophilic antibiotics. We also recorded the concurrent requirement for surgical intervention. Methodology , The clinical course of seventeen women with inflammatory breast disease and microbiologic and histologic evidence of infection with Corynebacterium kroppenstedtii were prospectively followed. 11 received treatment with doxycycline (or clindamycin if breast feeding), 5 women received alternative antibiotics, and one patient received no antibiotics. Results , Among the 11 who received doxycycline, full resolution without surgery of disease was achieved in 9 women while another woman showed improvement at follow up, further surgical management was required by 2. All the five women who received alternative antibiotics also had surgery. They each had full resolution of disease at follow up. Further admissions were required by one woman. Conclusion , Optimal treatment for granulomatous mastitis is yet to be determined. We found promising results with a small group of young women who were treated with the lipophilic antibiotic doxycycline alone. These had resolution of disease without requiring surgical intervention. [source] Apolipoprotein E,deficient mice are resistant to the development of collagen-induced arthritisARTHRITIS & RHEUMATISM, Issue 2 2010Darren L. Asquith Objective To determine whether elevated serum lipid levels resulting from feeding animals a high-fat diet can affect the inflammatory process in C57BL/6 (B6) wild-type (WT) and B6 ApoE,/, mouse models of collagen-induced arthritis (CIA). Methods Male B6 WT or ApoE,/, mice were fed either a normal chow diet or a high-fat diet. CIA was induced in mice at 12 weeks of age using type II chicken collagen, Freund's complete adjuvant, and, on occasion, a lipopolysaccharide boost. Expression levels of autoantibodies and cytokines were measured using enzyme-linked immunosorbent assay and multiplex assay, respectively. Results Whereas B6 WT mice developed severe articular inflammation after collagen immunization, ApoE,/, mice developed no clinical or histologic evidence of disease regardless of whether they had been fed a high-fat diet or a normal chow diet. The fact that arthritis was not present in ApoE,/, mice did not result from inadequate production of serum IgG2a collagen antibodies, since levels observed in ApoE,/, mice were similar to those observed in arthritic B6 WT control mice. Critically, development of atherosclerosis in ApoE,/, mice was not affected by the CIA protocol. Conclusion Our findings suggest that ApoE,/, mice are resistant to the development of CIA. Intriguingly, induction of host autoimmunity in the absence of articular inflammation had no effect on atherosclerosis progression, suggesting that articular inflammatory load may be a critical risk factor in vascular pathology. [source] Clinical and histologic evidence of salivary gland restoration supports the efficacy of rituximab treatment in Sjögren's syndrome,ARTHRITIS & RHEUMATISM, Issue 11 2009J. Pijpe Objective To assess the effect of rituximab (anti-CD20 antibody) therapy on the (immuno)histopathology of parotid tissue in patients with primary Sjögren's syndrome (SS) and the correlation of histologic findings with the flow rate and composition of parotid saliva. Methods In a phase II study, an incisional parotid biopsy specimen was obtained from 5 patients with primary SS before and 12 weeks after rituximab treatment (4 infusions of 375 mg/m2). The relative amount of parotid parenchyma, lymphocytic infiltrate, and fat, and the presence/quantity of germinal centers and lymphoepithelial duct lesions were evaluated. Immunohistochemical characterization was performed to analyze the B:T cell ratio of the lymphocytic infiltrate (CD20, CD79a, CD3) and cellular proliferation in the acinar parenchyma (by double immunohistologic labeling for cytokeratin 14 and Ki-67). Histologic data were assessed for correlations with the parotid flow rate and saliva composition. Results Four patients showed an increased salivary flow rate and normalization of the initially increased salivary sodium concentration. Following rituximab treatment, the lymphocytic infiltrate was reduced, with a decreased B:T cell ratio and (partial) disappearance of germinal centers. The amount and extent of lymphoepithelial lesions decreased in 3 patients and was completely absent in 2 patients. The initially increased proliferation of acinar parenchyma in response to inflammation was reduced in all patients. Conclusion Sequential parotid biopsy specimens obtained from patients with primary SS before and after rituximab treatment demonstrated histopathologic evidence of reduced glandular inflammation and redifferentiation of lymphoepithelial duct lesions to regular striated ducts as a putative morphologic correlate of increased parotid flow and normalization of the salivary sodium content. These histopathologic findings in a few patients underline the efficacy of B cell depletion and indicate the potential for glandular restoration in SS. [source] Decreased physical function and increased pain sensitivity in mice deficient for type IX collagenARTHRITIS & RHEUMATISM, Issue 9 2009Kyle D. Allen Objective In mice with Col9a1 gene inactivation (Col9a1,/,), osteoarthritis (OA) and intervertebral disc degeneration develop prematurely. The aim of this study was to investigate Col9a1,/, mice for functional and symptomatic changes that may be associated with these pathologies. Methods Col9a1,/, and wild-type mice were investigated for reflexes, functional impairment (beam walking, pole climbing, wire hang, grip strength), sensorimotor skills (rotarod), mechanical sensitivity (von Frey hair), and thermal sensitivity (hot plate/tail flick). Gait was also analyzed to determine velocity, stride frequency, symmetry, percentage stance time, stride length, and step width. Postmortem, sera obtained from the mice were analyzed for hyaluronan, and their knees and spines were graded histologically for degeneration. Results Col9a1,/, mice had compensatory gait changes, increased mechanical sensitivity, and impaired physical ability. Col9a1,/, mice ambulated with gaits characterized by increased percentage stance times and shorter stride lengths. These mice also had heightened mechanical sensitivity and were deficient in contact righting, wire hang, rotarod, and pole climbing tasks. Male Col9a1,/, mice had the highest mean serum hyaluronan levels and strong histologic evidence of cartilage erosion. Intervertebral disc degeneration was also detected, with Col9a1,/, mice having an increased incidence of disc tears. Conclusion These data describe a Col9a1,/, behavioral phenotype characterized by altered gait, increased mechanical sensitivity, and impaired function. These gait and functional differences suggest that Col9a1,/, mice select locomotive behaviors that limit joint loads. The nature and magnitude of behavioral changes were largest in male mice, which also had the greatest evidence of knee degeneration. These findings suggest that Col9a1,/, mice present behavioral changes consistent with anatomic signs of OA and intervertebral disc degeneration. [source] A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat modelsARTHRITIS & RHEUMATISM, Issue 7 2009Vijaykumar M. Baragi Objective Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad-spectrum MMP inhibitors developed for this purpose has been restricted by dose-limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP-13 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity. Methods Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA),induced OA was implemented for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP-13 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP-13 inhibitors have the joint toxicity associated with broad-spectrum MMP inhibitors. Results A number of non,hydroxamic acid,containing compounds that showed a high degree of potency for MMP-13 and selectivity against other MMPs were designed and synthesized. Steady-state kinetics experiments and Lineweaver-Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1-0635, indicated linear, noncompetitive inhibition, and Dixon plot analysis from competition studies with a zinc chelator (acetoxyhydroxamic acid) and ALS 1-0635 demonstrated nonexclusive binding. ALS 1-0635 inhibited bovine articular cartilage degradation in a dose-dependent manner (48.7% and 87.1% at 500 nM and 5,000 nM, respectively) and was effective in inhibiting interleukin-1,, and oncostatin M,induced C1,C2 release in human OA cartilage cultures. ALS 1-0635 modulated cartilage damage in the rat MIA model (mean ± SEM damage score 1.3 ± 0.3, versus 2.2 ± 0.4 in vehicle-treated animals). Most significantly, when treated twice daily with oral ALS 1-0635, rats with surgically induced medial meniscus tear exhibited histologic evidence of chondroprotection and reduced cartilage degeneration, without observable musculoskeletal toxicity. Conclusion The compounds investigated in this study represent a novel class of MMP-13 inhibitors. They are mechanistically distinct from previously reported broad-spectrum MMP inhibitors and do not exhibit the problems previously associated with these inhibitors, including selectivity, poor pharmacokinetics, and MSS liability. MMP-13 inhibitors exert chondroprotective effects and can potentially modulate joint pain, and are, therefore, uniquely suited as potential disease-modifying osteoarthritis drugs. [source] Role of CTA1R7K-COL-DD as a novel therapeutic mucosal tolerance,inducing vector for treatment of collagen-induced arthritisARTHRITIS & RHEUMATISM, Issue 6 2009Annemarie Hasselberg Objective To determine whether a cholera toxin,derived, novel immunomodulating fusion protein, CTA1R7K-COL-DD, carrying the class II major histocompatibility complex H-2q,restricted type II collagen peptide aa 259,274, can induce therapeutic tolerance and prevent collagen-induced arthritis (CIA) when administered intranasally in DBA/1 mice, and to assess whether ADP-ribosylation at the mucosal membranes exerts a regulatory function such that the outcome of tolerance or immune enhancement can be controlled. Methods DBA/1 mice with CIA were treated intranasally with CTA1R7K-COL-DD. The therapeutic effect was monitored for 46 days after the onset of disease. Clinical scoring of disease, histologic examination of inflammation, and bone erosion were assessed, and cytokine levels were determined in the serum or supernatants from splenocytes stimulated with recall antigen. Results The protective effect of CTA1R7K-COL-DD resulted in roughly 60% of the mice having no clinical signs or histologic evidence of disease after treatment, and those with CIA had significantly milder disease with less bone erosion. The protective status was associated with lower serum titers of IgG1, IgG2a, IgG2b, and IgG3 anticollagen and a substantial decrease in the production of interleukin-6 (IL-6), IL-17, and interferon-,, while levels of IL-10 were markedly up-regulated both in the serum and at the T cell level. Conclusion The enzymatically inactive mutant fusion protein CTA1R7K-COL-DD provided substantial therapeutic protection against CIA following intranasal administration. The mechanism behind the effect appears to be mediated by peptide-specific regulatory T cells induced by mucosal exposure to the peptide containing CTA1R7K-COL-DD vector. In addition, ADP-ribosylation at the mucosal membranes acts as a key regulator controlling mucosal tolerance or immunity. [source] Enhanced susceptibility to end-organ disease in the lupus-facilitating NZW mouse strainARTHRITIS & RHEUMATISM, Issue 4 2003Chun Xie Objective Although the NZW mouse strain is phenotypically normal, fulminant lupus glomerulonephritis (GN) develops when NZW mice are bred to several other strains, such as NZB, BXSB, B6.Sle1, and B6.Yaa. Based on the observation that aging NZW mice exhibit histologic evidence of GN, we sought to test our hypothesis that NZW mice may be more susceptible to immune-mediated renal damage. Methods NZW mice, as well as C57BL/6 (B6) and BALB/c control mice, were challenged with rabbit anti,glomerular basement membrane nephrotoxic sera (NTS), to induce renal disease. The different mouse strains were monitored for the degree of clinical disease, renal pathology, chemokine profiles, and cellular infiltrates. Results Although the NZW and control strains showed similar glomerular deposits of rabbit Ig and exhibited similar levels of anti-rabbit xenogeneic immune response, the NZW mice had significantly worse pathologic changes and disease. Compared with the control strains, the NTS-injected NZW mice demonstrated significantly increased proteinuria, elevated blood urea nitrogen levels, more severe histologic GN and tubulointerstitial nephritis, increased glomerular crescent formation with macrophage and neutrophil infiltrates, elevated expression of CC and CXC chemokines (monocyte chemoattractant protein 1, RANTES, KC), and significantly accelerated mortality. Importantly, these changes occurred within a few days after NTS administration. Finally, (B6 × NZW)F1 mice were as susceptible as the NZW parents, which indicates dominant NZW contributions. Conclusion Collectively, these findings support the notion that a lupus-facilitating genome may contribute to disease susceptibility by modulating the degree of immune-mediated end-organ damage. The availability of B6-based congenic strains bearing individual NZW-derived lupus susceptibility loci will permit future genetic dissection of end-organ susceptibility in murine lupus. [source] Anti-La/SSB antibodies transported across the placenta bind apoptotic cells in fetal organs targeted in neonatal lupusARTHRITIS & RHEUMATISM, Issue 6 2002Hai B. Tran Objective To determine whether La and/or Ro epitopes on apoptotic cells in fetal organs that are targeted in neonatal lupus syndrome (NLS) are accessible for binding by autoantibodies in vivo, we traced the fate of transplacental autoantibodies in a murine passive transfer model. Methods Pregnant mice at day 15 of gestation (E15) were injected intraperitoneally with human anti-Ro/La,positive sera or control sera, and transplacental transfer of human autoantibodies was tested by enzyme-linked immunosorbent assay with recombinant antigens. Multiple cryostat sections at the level of the heart of E17 fetuses were visualized simultaneously for human IgG binding and apoptosis (TUNEL) under confocal microscopy. Serial paraffin sections of E17 and E19 fetuses were examined for histologic evidence of inflammation. Results Human IgG anti,52-kd Ro, anti,60-kd Ro, and anti-La autoantibodies were transported efficiently into the fetal circulation. Human IgG,apoptotic cell complexes were detected in the heart (atrial trabeculae and atrioventricular node), skin, liver, and newly forming bone of fetuses from mothers injected with anti-Ro/La sera but not control sera. The IgG binding was fetal-specific and organ-specific; transplacental autoantibodies did not bind to apoptotic cells in the fetal thymus, lung, brain, or gut. The complexes were not associated with an inflammatory reaction. Injection of mothers with affinity-purified anti-La autoantibodies (but not anti-Ro/La Ig depleted of anti-La) revealed an identical location of IgG binding to apoptotic cells in the fetuses. Conclusion This is the first study to demonstrate that transplacental anti-La autoantibodies bind specifically to apoptotic cells in selected fetal organs in vivo, similar to the organ involvement in NLS. We hypothesize that additional factors are required to promote proinflammatory clearance of IgG,apoptotic cell complexes and subsequent tissue damage. [source] Serum alanine aminotransferase levels and survival after hepatectomy in patients with hepatocellular carcinoma and hepatitis C virus-associated liver cirrhosisCANCER SCIENCE, Issue 12 2003Kazuo Tarao We examined whether sustained alleviation of inflammation as monitored by serum alanine aminotransferase (ALT) levels was associated with longer survival in hepatectomized hepatocellular carcinoma (HCC) patients with hepatitis C virus-associated liver cirrhosis (HCV-LC). Thirty-four hepatectomized patients with HCV-LC and HCC as a single nodule, and for whom more than 5 years had elapsed after the hepatectomy, were studied. They had no histologic evidence of portal or hepatic vein invasion. They were subdivided into two groups according to their serum ALT levels in the 2 years after hepatectomy: the low ALT group comprised 13 patients whose serum ALT levels showed a sustained low level below 80 IU, and the high ALT group comprised 21 patients whose serum ALT levels showed several peaks or plateaus above 80 IU. The patients had been followed-up prospectively with frequent ultrasonography and magnetic resonance imaging or computed tomography for recurrence for >5 years. The survival period, non-recurrence interval and number of recurrences were observed. Recurrences were treated with transcatheter chemoembolization in all cases. The cumulative survival rate in the low ALT group was significantly better than that in the high ALT group (P<0.05). The 5-year survival in the low ALT group was as high as 92.3% (12 of 13) compared with 33.3% (7 of 21) in the high ALT group (P<0.05). The cumulative non-recurrence rate in the low ALT group was also significantly better than that in the high ALT group (P<0.01). The survival period correlated well with the interval until the first recurrence (r=0.545, P=0.006). There was a tendency for the number of recurrences in the low ALT group (1.5±0.4, mean±SE) to be fewer than that in the high ALT group (2.2±0.4), although this was not significant. Sustained alleviation of inflammation, as indicated by low ALT levels, provides a survival advantage mainly due to the longer non-recurrence interval, and possibly because of fewer recurrences, in hepatectomized HCC patients with HCV-LC. [source] A Study of Moderately Differentiated Neuroendocrine Carcinomas of the Larynx and an Examination of Non-Neoplastic Larynx Tissue for Neuroendocrine CellsTHE LARYNGOSCOPE, Issue 7 2004Jin-Haeng Chung MD Abstract Objectives/Hypothesis: To determine the most appropriate terminology for neuroendocrine carcinomas (NEC) of the larynx, successive clinicopathologic studies are encouraged. The typical location and immunophenotype of laryngeal NEC raise a question of whether any precursor cells exist. Study Design: Six patients with laryngeal NEC were analyzed. Another 20 laryngectomy specimens were examined for the presence of non-neoplastic neuroendocrine cells. Methods: Tumor morphology and patient outcome were determined, and tumor tissue underwent immunohistochemical examination to identify cytokeratin, neuroendocrine markers (chromogranin, synaptophysin, CD56, calcitonin), S-100 protein, and p53 protein. A neuroendocrine marker study was also performed on non-neoplastic regions of another 20 laryngectomy specimens to identify any neuroendocrine cells. Results: Laryngeal NEC, all submucosal, exhibited various morphology with or without histologic evidences of neuroendocrine differentiation. The tumors showed frequent (67%) calcitonin expression, calcitonin secretion in one case, and common (50%) p53 over-expression. Three patients died within 3 years. In the non-neoplastic larynx specimens, Kulchitsky cell-like bipolar neuroendocrine cells were identified in the basal and middle layer of the respiratory epithelium of the ventricle and subglottis but none in the submucosal layer of the supraglottic region. The neuroendocrine cells did not express calcitonin. Conclusions: Moderately differentiated or large-cell NEC is a more favored term than atypical carcinoid until more refined classifications for upper respiratory tract NEC are agreed on. Despite the confirmed presence of neuroendocrine cells in the respiratory epithelium of the larynx, the origin of laryngeal NEC remains unknown. p53 mutation might be one of the major molecular steps in the pathogenesis of laryngeal NEC. [source] | ||||||||||||||||||||||