Microsatellite variation in the Australian dingo

Shoulder arthroplasty (SA) is commonly performed in patients with rheumatoid arthritis (RA) who have been treated with long-term immunosuppressive medication. RA is associated with an increased risk of neoplasms of the immune system. A case of non-Hodgkin's lymphoma as an unexpected diagnosis after the routine pathologic examination of the soft tissues after SA was detected in a 54-year-old woman with long-standing RA and prolonged immunosuppressive therapy. Although this case does not support the cost-effectiveness of routine specimen evaluation during SA, we suggest that histological analysis of the surgical tissues is appropriate and should be performed in all patients who have been treated with prolonged immunosuppressive medication, especially RA patients as well as patients who have suspicious surgical findings.     

Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance?

We identified 68 patients with clonal T-large granular lymphocyte (T-LGL) proliferations who were seen at the Mayo Clinic between 1984 and 1992. Nineteen (28%) were asymptomatic at diagnosis, while the rest experienced fatigue (60%), B-symptoms (12%), and recurrent infections (15%). Associated comorbid conditions included rheumatoid arthritis (RA) in 26%. Severe anemia (hemoglobin [Hb] < 8g/dL) and neutopenia (absolute neutrophil count [ANC] < 500/microL) were seen in 19% and 40% of patients, respectively. Immunophenotypic studies showed CD3+, CD8+ phenotype in the majority (72%). Twenty-one patients (31%) have required no therapy, and remain relatively stable with a median follow-up period of 50 months. Treatment was required at either diagnosis (36 patients) or at subsequent follow-up (11 patients). Initial response rates were similar in patients treated with cyclophosphamide (CTX) with or without prednisone (69%), or prednisone alone (73%). Overall, 61 patients (90%) are alive with a median follow-up of 44 months. Actuarial median survival of this entire cohort is 161 months. The presence of anemia or symptoms does not appear to correlate with the tumor burden. In patients requiring therapy, a lower ANC and the presence of B-symptoms/infection were independently associated with a significantly lower probability of achieving a molecular or hematologic complete remission (H-CR). Intermittent immunosuppressive therapy is effective in achieving durable responses in a number of patients. T-LGL proliferations are associated with a favorable prognosis and response to therapy. However, significant heterogeneity exists in clinical presentation and associated comorbid conditions. These disorders should be included in the differential diagnosis of patients with unexplained cytopenias, particularly in the setting of RA and other autoimmune disorders. Analogous to the situation with monoclonal gammopathies, a term such as T-cell clonopathy of undetermined significance (TCUS) may be more appropriate to describe these patients.     

D-penicillamine induced myasthenia gravis: clinical, serological and genetic findings

Eight cases of D-penicillamine (DP) induced myasthenia gravis (MG) are presented. Seven patients were being treated for rheumatoid arthritis (RA) and one for scleroderma. The mean duration of DP treatment until the myasthenic symptoms developed ranged from 2-8 months. The DP dose reached 500 mg daily. It was found that the clinical and immunological findings were almost similar to those of idiopathic MG, but were less severe. All patients had increased titers of acetylcholine receptor antibodies in their sera. Discontinuation of D-penicillamine resulted in the complete resolution of myasthenic symptoms after 2-6 months. One patient required ventilation, immunosuppressive therapy and plasma exchange. No association was found between DP related MG and the various autoantibodies tested. Immunogenetic analysis showed that three patients had HLA-DR1, two HLA-DR3, one HLA-DR4 and one HLA-DR5. In conclusion, the clinical presentation of DP-induced MG seems similar to idiopathic MG. DP-related MG is relatively benign, although it sometimes can cause life-threatening muscle weakness requiring aggressive therapy. The relatively small number of patients included in this study, however, does not permit any firm conclusions regarding the HLA associations of DP-related MG.     

Tumors of the papilla of Vater--diagnostic and therapeutic dilemmas

Benign and malignant tumors of papilla Vateri are rare diagnoses in the endoscopic practice. Sixteen patients with benign and 22 cases of malignant tumors are presented. In all of them endoscopic cholangiopancreatography with or without papillotomy followed by biopsy and operation in 13 cases was performed. Biopsy confirmed the endoscopy in 71%. Adenomyosis, supposed by endoscopy was proved by repeated histology in only 2/9 cases although invasive component of the tumor was found in 3/9 patients at operation underlying precancerous nature of this entity. Among 5 cases of villous adenoma one developed malignant alterations during 4 years of follow-up. Biopsy was not more effective after papillotomy than without it, and 5-7 days of delay for recovery of thermic lesion did not ameliorate success rate of histology. For malignant diseases surgical therapy should be considered if staging of tumor and general condition of the patient permits. In unresectable cases endoscopic palliation (papillotomy or polypectomy with or without drainage) can increase survival. In patients with benign tumors operative endoscopy followed by regular ultra-sonography and endoscopy seems to be necessary.     

Optimal treatment in gestational trophoblastic disease

Gestational trophoblastic diseases are a heterogenous group of conditions ranging from the benign hydatidiform mole to the malignant choriocarcinoma. Optimal therapy in this group of diseases rest in the correct diagnosis, assessing their risk for malignant behavior using prognostic scoring systems and administering appropriate treatment. Their rarity makes it imperative that these patients are treated in special centres by experts. Benign moles are treated surgically with evacuation of the uterus or hysterectomy. In malignant gestational trophoblastic disease, chemotherapy is the treatment of choice; single agent for non-metastatic and low-risk metastatic disease and combination chemotherapy for high-risk metastatic disease. Judicious use of surgery and radiotherapy in these cases will improve the survival rate. With appropriate treatment, the cure rates approach 100% in the low-risk group and 80% to 85% in the high risk group.     

No increased risk of malignancies and mortality in cyclosporin A-treated patients with rheumatoid arthritis

OBJECTIVE: To evaluate the cyclosporin A (CSA)-attributed risk of developing malignancies in general and malignant lymphoproliferative diseases (LPDs) and skin cancers in particular, as well as the CSA-attributed incidence of mortality in patients with rheumatoid arthritis (RA). METHODS: In a retrospective, controlled cohort study, the incidence of malignancies and mortality was evaluated in 208 CSA-treated patients with RA compared with 415 matched control patients with RA between 1984 and 1995. Patients were followed up for a median of 5.0 years (range 1.4-12.0). RESULTS: Forty-eight cases of malignancy (8 in the CSA group and 40 in the control group; relative risk [RR] 0.40, 95% confidence interval [95% CI] 0.19-0.84) were identified, of which 8 were malignant LPDs (2 CSA versus 6 control; RR 0.67, 95% CI 0.14-3.27) and 14 were skin cancers (2 CSA versus 12 control; RR 0.33, 95% CI 0.08-1.47). Seventy-three patients died (16 CSA versus 57 control; RR 0.56, 95% CI 0.33-0.95) due primarily to cardiovascular diseases (4 CSA versus 22 control; RR 0.36, 95% CI 0.13-1.04) or a malignancy (3 CSA versus 8 control; RR 0.67, 95% CI 0.18-2.43). Proportional hazards regression analysis with correction for potential confounding factors did not significantly change the results. CONCLUSION: The study findings suggest that CSA treatment in RA patients does not increase the risk of malignancies in general or the risk of malignant LPDs or skin cancers in particular. Moreover, the incidence of mortality in CSA-treated RA patients was comparable to that in matched control RA patients.     

Benign thyroid oncocytomas. Outcome after more than 4 years

OBJECTIVES: Occasional malignant transformation after partial thyroidectomy for Hürthle cell tumours has led certain authors to propose total thyroidectomy in all cases. The aim of this retrospective study was to evaluate outcome 4 years after partial thyroidectomy in patients with Hürthle cell tumours. METHODS: Ten patients (9 females, 1 male; mean age 45 years; age range 21-65 years) underwent thyroid surgery for Hürthle cell tumours from 1980 to 1989. Lobectomy was performed in 7, subtotal thyroidectomy in 2 and tumourectomy in 1. The extemporaneous pathology examination reported 4 apparently benign vesicular lesions, 2 apparently benign oncocyte lesions, 2 fetal adenomas, 1 thyroiditis, 1 trabecular adenocarcinoma. Pathology examination of the surgical specimen reported isolated benign oncocyte tumours in 4 cases and benign oncocyte tumours with associated vesicular adenomas in 5. In 1 case it was not possible to confirm whether the oncocyte lesion was benign or malignant. All 10 patients were seen again 6 months later for consultation and thyroid hormone assays and thyroid echography in doubtful cases. RESULTS: All patients were seen for follow-up (mean 88 months; range 47-148 months). New thyroid nodules were observed in 2 but did not require surgery. No cervical lymph node enlargement was found. CONCLUSION: The diagnosis of Hürthle cell tumour was confirmed intraoperatively in 8 of the 10 cases. No malignant transformation was observed. These findings demonstrate that total thyroidectomy cannot be indicated intraoperatively and would not appear to be indicated after partial thyroidectomy.     

Lack of immunosuppressive effect of low-dose oral methotrexate on lymphocytes in rheumatoid arthritis

Whether methotrexate (MTX) is effective in rheumatoid arthritis (RA) because of immunosuppressive and/or anti-inflammatory mechanisms of action is controversial. Many lines of investigation point to the latter. We evaluated DNA synthesis in peripheral blood lymphocytes (PBL) from 33 RA patients on oral MTX (7.5-15 mg/wk) and in 30 healthy controls by flow cytometric cell cycle analysis (CCA). DNA synthesis was also evaluated with a thymidilate synthetase activity assay (TSA) (3H-deoxyuridine incorporation) in 12 patients and 21 controls (12 on MTX and NSAID, and 9 healthy subjects). The patients had taken MTX for at least 3 months and were in different stages of clinical activity. There were no significant differences in TSA or in the cell cycle phase distributions (especially the S phase) between treated RA patients and controls. These data suggest that low-dose oral MTX does not inhibit DNA synthesis and therefore does not have an immunosuppressive effect on lymphocytes from patients with RA.     

Fluoride therapy in prevention of rheumatoid arthritis induced bone loss

OBJECTIVE: To determine the efficacy of sodium fluoride (40 mg/day) in preventing rheumatoid arthritis (RA) induced bone loss, which may lead to osteoporosis. METHODS: We conducted an 18 month, randomized, double blind, placebo controlled trial in 38 patients with RA. The primary outcome measure was the difference in the percentage change between groups in lumbar spine bone mineral density (BMD) from baseline values after 18 months of therapy. The secondary outcome measures were the differences in the percentage change between groups in femoral neck, Ward's triangle, trochanter, and total body BMD from baseline after 18 months of therapy. RESULTS: There was a significant percentage difference (SD) between groups of 6.2% (7.3%) (p = 0.0005) in lumbar spine BMD after 18 months of treatment in favor of the fluoride group. The fluoride group experienced a 5.2% (8.4%) (p = 0.0125) increase, whereas the placebo group showed a 1.0% (4.8%) (p = 0.8015) decrease in lumbar spine BMD after treatment. No significant differences were found for the femoral neck, Ward's triangle, trochanter, and total body BMD in terms of the percentage changes from baseline within each treatment group or in the differences in the degree of change between groups after therapy. Lumbar spine BMD increased in about 80% of patients treated with fluoride (responders) compared to 44% of patients treated with placebo. CONCLUSION: The results showed that fluoride therapy was well tolerated and increased vertebral bone mass in patients with RA.     

Incidence of acral nodulosis with long-term methotrexate therapy in patients with inflammatory rheumatic diseases

The significance of acral nodulosis under methotrexate therapy is still controversial. Among patients with rheumatoid arthritis and methotrexate therapy this manifestation could be observed in 8/163 (5%). All cases were seropositive and already treated with other LAAD. Patients with other inflammatory rheumatic diseases under methotrexate therapy (n = 83) did not develop this nodulosis. The acral nodulosis is interpreted as a typical side-effect of methotrexate only in patients with rheumatoid arthritis. Histopathologically, these nodules do not differ from the typical rheumatoid nodule.     

The treatment and prognosis of patients with phyllodes tumor of the breast: an analysis of 170 cases

BACKGROUND: The study addresses the controversial prognostic and therapeutic aspects of phyllodes tumor of the breast. METHODS: Records of 170 women with phyllodes tumor of the breast were reviewed. On the basis of the criteria proposed by Azzopardi and Salvadori et al., including estimation of tumor margin, growth of the connective tissue component, mitoses, and cellular atypia, the entire series was divided into three histotypes of phyllodes tumor, i.e., benign (92 cases, 54.1%), borderline (19 cases, 11.2%), and malignant (59 cases, 34.7%). Ninety-eight patients (57.6%) were treated by wide local excision (79 benign, 15 borderline, and 4 malignant), 43 (25.3%) by simple mastectomy (13 benign, 4 borderline, and 26 malignant), and 29 (17.1%) by radical mastectomy (all malignant). RESULTS: Of the 170 treated patients, 141 (82.9%) survived 5 years without evidence of disease. In the Cox multivariate analysis the histotype of the tumor was the only independent prognostic factor: 5-year NED survival was observed in 95.7% of the patients with benign phyllodes tumor, 73.7% with borderline phyllodes tumor, and 66.1% with malignant phyllodes tumor. After a wide local excision 98.7% of the patients with benign tumor, and 80% with borderline tumor, were cured. Local recurrence was found in 14 patients (8.2%) (4 benign, 3 borderline, and 7 malignant); 10 of these underwent reoperation (7 wide local excision, 3 radical mastectomy) and survived 5 years NED. CONCLUSIONS: The histotype of phyllodes tumor (benign, borderline, and malignant), assessed on the basis of the criteria proposed by Azzopardi and Salvadori et al., was the only prognostic factor in our group of patients. Based on the data from literature and our own observations, we observed that a wide local excision, with an adequate margin of normal breast tissue, is the preferred initial therapy for phyllodes tumor of the breast.     

Can manipulation of a pelvic tumour influence the serum level of cancer antigen 125 and cancer-associated serum antigen?

Cancer antigen 125 (CA 125) and cancer-associated serum antigen (CASA) were measured in 24 women with pelvic masses before and after a gynaecological examination and ultrasonography. CA 125 decreased median 16% after manipulation (P < 0.0001) and CASA decreased median 8% (P = 0.0077). The decline was found in patients with benign tumours as well as in patients with malignant tumours.     

Epidemiological study of benign tumors and inflammatory pseudotumors of the eye and its adnexa

PURPOSE: Benign tumors and the inflammations of the eye and its adnexa are about twice as frequent as malignant tumours. Because of the aesthetic value or functional importance and the diagnostic difficulties that they can induce, we thought it interesting to conduct an epidemiological study including the localization and the different histological forms of benign tumors and inflammations of theeye. MATERIAL AND METHODS: This study was carried out for a period of 70 years between 1925 and 1995, utilizing case histories and results of the histological examinations of the Pathology Department of the Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts in Paris. The statistics included the histological diagnostic, the localization and the civil data. RESULTS: Benign tumors and inflammations of the eye and its adnexa corresponded respectively to 25.9% and 7.1% of the histological results accomplished in the laboratory. Papilloma (31.4%) and cysts (28.2%) were the most frequent benign tumors. Chalazions represent the most frequent aetiology of inflammation (49%), followed by granuloma (30%). Our results are compared to those of other laboratories. CONCLUSION: While malignant tumors account for the majority of endo-ocular tumors, benign tumors and inflammatory processes are almost always extra-ocular involving the conjunctiva and the eye lids (in particular the inferior eye lid). Papilloma and cysts together account for about 50% of the benign tumors and inflammations of the eye.     

Isolated middle lobe atelectasis: aetiology, pathogenesis, and treatment of the so-called middle lobe syndrome

Isolated atelectasis of the middle lobe has been known for many years as the "middle lobe syndrome". Several clinical studies have shown that it may bae caused by malignant tumours. A 10-year study of 135 patients with isolated middle lobe atelectasis is presented. Fifty-eight patients (43%) had malignant tumours. Of 38 who had a thoracotomy, lung resection was possible in 25. In 20 patients regional or systemic dissemination of the tumour had been diagnosed before operation. Seventy-seven patients had benign diseases, of which 74 were non-specific infections. Bronchography was performed in 46 of these cases, and all had abnormal findings in the middle lobe, eight revealing definite bronchiectasis. In three cases tuberculosis was found. In 16 cases the benign diagnosis was established at thoracotomy. Only three patients out of 58 with malignant tumours lived more than five years. Atelectasis of the middle lobe is always a sign of potential malignancy especially in patients with a previously normal chest radiograph.     

Incidence of primary bone tumours and tumour like lesions in and around Dakshina Kannada district of Karnataka

A total of 523 cases of primary bone tumours and tumour like lesions in and around Dakshina Kannada district of Karnataka were diagnosed over a period of 36 years. About 39% of these tumours were malignant and the remaining benign. Among the malignant tumours the highest incidence was of osteosarcoma (45.7%) followed by Ewing's sarcoma (19.4%). Osteochondroma was the most frequent in the benign tumour category (30.3%). Peak incidence of tumour was in the 2nd and 3rd decade of life with a male preponderance. The most commonly affected bones were femur, tibia and humerus in that order. Results indicate a significantly higher incidence of primary bone tumours in this part of India.     

Discordant twins with Parkinson''s disease: positron emission tomography and early signs of impaired cognitive circuits

Anti-neutrophil cytoplasmic antibodies (ANCA) in sera from 52 patients with rheumatoid arthritis (RA), including 9 patients with malignant RA (MRA) and 20 healthy controls were examined by indirect immunofluorescence technique (IIF). Nine out of 52 RA patients showed positive ANCA staining. None of MRA patients had, however, ANCA in sera. The staining pattern for ANCA was either perinuclear for 4 sera or non-specific for 5 sera, but not cytoplasmic. Furthermore, anti-nuclear antibodies (ANA) in 9 ANCA positive RA sera were tested by IIF, using Hep-2 cells. Six sera had positive ANA. Three sera showed as nucleolar and 1 serum as centromere in ANA staining pattern. The incidence of these ANA staining pattern in ANCA positive sera (4 out of 9) was higher than in ANCA negative sera (1 out of 19). The clinical profiles and laboratory findings of 9 RA patients with positive ANCA revealed that they had suffered and treated for more than 10 years and had still active joint inflammation, like intractable RA. These results indicate that ANCA in RA are not associated with vasculitis.     

Production of urokinase-type plasminogen activator (u-PA) and plasminogen activator inhibitor-1 (PAI-1) in human brain tumours

We investigated the role of plasminogen activators (PAs) and their inhibitor (plasminogen activator inhibitor-1, PAI-1) in human brain tumours. The amounts of urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1), and the activity of u-PA and t-PA were determined by enzyme-linked immunosorbent assay (ELISA), and u-PA and PAI-1 were immunolocalized using monoclonal antibodies in human brain tumours and normal brain tissues. The tissues were surgically removed from 64 patients; normal brain tissue (5 cases), low-grade glioma (4 cases), high-grade glioma (17 cases), metastatic tumour (9 cases), meningioma (benign 12 cases, malignant 6 cases), acoustic schwannoma (11 cases). u-PA activity and u-PA and PAI-1 antigen levels were significantly elevated in malignant brain tumours (malignant meningiomas, high-grade gliomas, and metastatic tumours) and acoustic schwannomas but very low in benign meningiomas, low-grade gliomas and normal brain. There was no difference in t-PA antigen levels among normal and malignant tissues, however levels of t-PA activity were markedly decreased in metastastic tumours. All malignant brain tumour tissues showed positive immunostaining for u-PA and PAI-1, however, some tumour cells showed negative intensity while others showed strong intensity for these antibodies. This contrasts to the homogeneous staining pattern found in acoustic schwannoma. These findings indicate that malignancy in human brain tumours is associated with elevated levels of u-PA and PAI-1 and that an imbalance between these proteins in a micro-environment contributes (ascribes) to tumour cell invasion.     

Sacrococcygeal germ-cell tumours--the Red Cross War Memorial Children's Hospital experience, 1980-1996

OBJECTIVE: To document the experience of Red Cross War Memorial Children's Hospital in the treatment of sacrococcygeal germ-cell tumours. PATIENTS: Twenty-seven patients with sacrococcygeal germ-cell tumours were treated in our hospital from 1980 to 1996. DESIGN: A retrospective review of these patients' records was undertaken. RESULTS: There were 19 female and 8 male patients. Seventeen (63%) presented in the neonatal period, 13 on the first day of life. Complete surgical resection of the tumour was achieved in all patients with mature or immature teratomas (20 patients) and in 2 neonates with malignant tumours. The first of these 2 neonates, with a malignant teratoma, was not given chemotherapy and remains well 10 years later. The second, with a yolk-sac tumour, also received no initial chemotherapy. He relapsed at the age of 9 months and was successfully treated with repeat excision and chemotherapy. All 5 patients first diagnosed after the age of 1 year had malignant tumours. These patients had incomplete surgical resection (3) or biopsy only (2), and 3 were successfully treated with chemotherapy. One patient relapsed with yolksac tumour after initial complete resection of a mature teratoma. She was successfully treated with repeat surgery and chemotherapy.     

Defective proximal tubule lysosomal acidification by Bence Jones proteins. An immunoelectron microscopy study

AIMS: To determine their significance, we examined the expression pattern of the four epidermal growth factor receptor (EGFR) family members as well as the phosphotyrosine kinase activity in breast tumour tissues. METHODS AND RESULTS: Fifty-three malignant breast tumours, four breast cancer cell lines, and 10 benign breast tumours were investigated. Fifty-three per cent (28/53) of the malignant tumours expressed EGFR protein, and the majority of these positive tumours were strongly positive. Eighty per cent (8/10) of the benign tumours also expressed EGFR protein, but all in a lower or moderate level. An association between EGFR expression and increasing malignancy grade was found in the group of infiltrating ductal carcinomas. Of the malignant tumours, 35.8% (19/53) expressed c-erbB-2 protein and 17% (9/53) c-erbB-3 protein, while no expression of c-erbB-2 and c-erbB-3 proteins was found in the benign tumours. Contrary to previous reports, we observed c-erbB-4 receptor protein to be less expressed in the malignant breast tumours. The 'normal' breast epithelial cells adjacent to the malignant tumours and the benign tumours demonstrated intensified membrane staining for c-erbB-4, while a number of the malignant tumours demonstrated a weak cytoplasmic staining or were negative. However, several malignant tumours with strong membrane staining for the c-erbB-4 protein were also found. No simple association between the expression of the four receptors and phosphotyrosine kinase activity was found. CONCLUSION: Our study has revealed a complex expression pattern of the EGFR family members in breast tumour cells. While the data about EGFR, c-erbB-2, c-erbB-3 and phosphotyrosine are largely in line with what has been reported, we found the c-erbB-4 protein expression to be decreased in the malignant tumours.     

Solitary thyroid nodules. Separating benign from malignant conditions

Although features found on history taking, physical examination, thyroid function tests, and imaging studies help categorize solitary thyroid nodules as benign or malignant, fine-needle aspiration biopsy is the diagnostic test of choice. Nodules found to be malignant on cytologic examination should be treated with surgery. Benign nodules may be followed clinically or treated with levothyroxine to suppress their growth. Intermediate nodules should be excised if there is clinical suspicion of malignancy. In suspect nodules, levothyroxine therapy with follow-up ultrasound assessment for size is appropriate. Nodules that do not shrink significantly within 6 months should be excised.