In SAPHO syndrome anti-TNF-alpha therapy may induce persistent amelioration of osteoarticular complaints, but may exacerbate cutaneous manifestations.

OBJECTIVES: SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis and osteitis) is a rare disease combining skin, bone and joint manifestations. In recent years new therapeutic strategies have been tried, among them TNF-alpha-blocking agents. We report our experience with infliximab in four cases of SAPHO syndrome refractory to conventional therapies. METHODS: Between 2002 and 2005, four cases of SAPHO syndrome (two females and two males; mean age 49.7 yr) responding poorly to conventional drugs were treated with infliximab. The dose was 5 mg/kg, according to the protocol used in spondyloarthropathies, with infusions at 0, 2 and 6 weeks followed by 6 weeks intervals. No active cutaneous manifestations were present at the time of starting therapy. RESULTS: Complete remission of osteoarticular involvement was achieved after the second or third infusion, and the positive response was maintained for up to 12 months. A patient relapsed after discontinuation of infliximab, because of infectious complication. Palmoplantaris pustulosis relapsed in two patients after three and six infusions, respectively; there was slight improvement after discontinuation of anti-TNF-alpha drugs. CONCLUSIONS: Infliximab seems to be a very effective therapy for osteoarticular complaints of SAPHO syndrome. Cutaneous involvement responded less favourably, palmoplantaris pustulosis relapse being a possible complication.

Multicentric reticulohistiocytosis: a rare cause of erosive arthropathy of the distal interphalangeal finger joints.

BACKGROUND: Multicentric reticulohistiocytosis (MRH) is a rare systemic disease, presenting with typical skin abnormalities and erosive polyarthritis, which is often associated with malignancy. CASE REPORT: A case of MRH arthropathy, in which the typical nodular skin manifestation of the disease was absent, is described in a patient with a past history of breast cancer and no evidence of recurrent or new malignancy. RESULTS: Careful clinical and roentgenological evaluation disclosed important clues to differentiate this condition from other more common distal interphalangeal arthritides--namely, osteoarthritis and its "erosive" variant, rheumatoid arthritis, psoriatic arthritis, tophaceous gout, dialysis related hand arthropathy, and from the rarer fibroblastic rheumatism, all of which can be mimicked by MRH. Histopathology showed the characteristic histiocytic and multinucleated giant cell infiltrate with ground glass cytoplasm, and immunohistochemical analysis showed markers evocative of a monocyte/macrophage origin of MRH.

HBV-related cutaneous periarteritis nodosa in a patient 16 years after renal transplantation: efficacy of lamivudine.

Cutaneous periarteritis nodosa (PAN) is a clinical feature characterized by chronic, benign course; its pathogenesis is unknown. In patients submitted to renal transplantation cutaneous PAN is a rare complication. We report a case of cutaneous PAN associated with the reappearance of hepatitis B antigen 16 years after kidney transplantation. A 44-year-old man underwent successful renal transplantation in June 1980. In December 1996 he presented multiple painful erythematous subcutaneous nodules on both legs. Skin lesion biopsy showed the presence of cutaneous PAN. Six months later laboratory data demonstrated the presence of HbsAg. HBeAg, HBcAb and detectable HBV-DNA serum by polymerase-chain-reaction (PCR) assay. Anti-HBs and anti-HBe proved negative. In July 1998 the laboratory tests showed an important increase of HBV-DNA (5.1 billion by Branched DNA), and so lamivudine (100 mg/day) was introduced. HBV-DNA became undetectable by PCR after 3 months of therapy. Seven months later a new skin biopsy was performed. The typical signs of PAN were no longer evident. As HBV infecion was demonstrated six months after the clinical appearance of the PAN, in a patient who was believed to be immune to the virus, it is possible that, in the early stages, the hepatitis B antigen title was methodologically indeterminable, but sufficient to form circulating immune complexes responsible for vasculitis primer. Lamivudine therapy resulted efficacious in favouring the regression of cutaneous PAN, but its long-term efficacy requires further evaluation as regards potential selection of drug resistant hepatitis B virus (HBV) mutants during treatment.

A novel recurrent translocation t(11;14)(p11;q32) in splenic marginal zone B cell lymphoma.

A novel recurrent translocation t(11;14)(p11;q32) was found in three patients with splenic marginal zone B cell lymphoma (MZBCL). Fluorescence in situ hybridization (FISH) studies with IgH probes revealed in all cases involvement of the IgH locus, with breakpoint downstream of the IGVH sequences. Partner genes at 11p11 were not identified. The translocation defined the stem line in two patients, who carried additional cytogenetic aberrations, including a 17p deletion, present in both cases. In one patient a 7q- chromosome was the primary cytogenetic defect, the t(11;14) having been found in four out of 11 abnormal metaphase cells at the time of transformation into high-grade MZBCL. Hematological features in all cases included splenomegaly with peripheral blood (PB) involvement by a monoclonal B cell population consisting of lymphocytes with villous projections and several blast-like cells. The immunophenotype was CD19+; CD22bright+; CD23-, CD10-, CD5-, surface Igbright+. A bone biopsy in one patient revealed an interstitial infiltration with an intrasinusoidal pattern of growth. Histological studies on spleen specimens in two patients showed an expanded marginal zone, with small lymphocytes and several blast-like cells. One patient had a therapy-demanding disease, with partial, short-term responses to cytotoxic treatment; one patient transformed into a high-grade MZBCL involving the gut, the PB and the bone marrow 2 years after diagnosis; one patient was unresponsive to cytotoxic treatment and underwent splenectomy. The t(11;14)(p11;q32) may define a subset of splenic MZBCL with a high-grade component and a relatively aggressive clinical behavior.

Molecular cytogenetic characterization of marginal zone B-cell lymphoma: correlation with clinicopathologic findings in 14 cases.

BACKGROUND AND OBJECTIVES: To improve the definition of the incidence and significance of chromosome lesions occurring in marginal zone B-cell lymphoma (MZBCL). DESIGN AND METHODS: Fourteen cases of MZBCL diagnosed according to the REAL classification were studied by conventional chromosome analysis (CCA) and by interphase fluorescence in situ hybridization (FISH) using the following probes: 3q27/BCL6, 6q21, 7q31, 9p21/p16, 11q22/ATM, 13q14, 17p13, centromeres of #3, #7, #12. Pertinent clinical data were collected. RESULTS: Primary disease presentation consisted of histologically documented splenic MZBCL in 9 cases, nodal MZBCL in 3 cases and extra-nodal MZBCL in 2 cases. Four cases showed evolution into a high-grade lymphoma, due to the presence of a predominant large cell or blast cell component. Clonal karyotype anomalies were detected by CCA in 12 cases, 6 of which had a complex karyotype, including all 4 cases with high-grade histology. Interphase FISH confirmed cytogenetic data and revealed several cryptic chromosomal lesions. Overall, total/partial +12 was found in five cases; 13q14 and 17p13 deletion were found in four cases each; +3, 7q31 deletion and a BCL6 split signal were found in three cases; deletions at 6q21 and 11q22.3 in two cases each; +7 and a 9p21 deletion were found in one case each. INTERPRETATION AND CONCLUSIONS: i) Besides +3 and 7q-, 13q14 deletion, total/partial +12, BCL6 rearrangement, and deletions at 6q21, 11q22-23, and 17p13.3 are relatively frequent events in MZBCL; ii) unlike in mantle cell lymphoma, 9p21 deletion occurred infrequently in MZBCL; iii) a switch into high grade histology is usually associated with complex chromosome defects, including 6q-, 11q-, +12, and 17p.

LOH of chromosome 6q compared with LOH of 17q and 18q in ovarian cancers: relationship to p53 expression and clinicopathological findings.

In 41 ovarian epithelial tumors (7 borderline and 34 invasive), loss of heterozygosity (LOH) of chromosomes 6q, 17q, and 18q was examined using 4 microsatellite markers: ER (6q 25-1), BRCA1 (17q21), DCC (18q21), and D18S58 (18q23). The LOH was compared with clinicopathological findings, including p53 and ER expression. In borderline tumors, LOH and p53 expression were never found, while in invasive carcinomas LOH and p53 were found in 71% and 59% of cases, respectively. In particular, in invasive carcinomas 6q LOH represented a marker distinguishing two groups of tumors; those with 6q LOH were only of serous histotype and at advanced stages (III/IV). No significant difference was found for any of genes in 5-year survival of the patients. No correlation was found between ER expression and ER LOH, as well as between biological aggressiveness and 17q and/or 18q LOH. We conclude that p53 and LOH of the investigated loci distinguish borderline from invasive ovarian carcinomas; moreover, the comparison of these results with clinicopathological parameters suggests that the presence of 6q LOH may be a factor accounting for greater biologic aggressiveness independent of the histologic subtype.

Evidence for androgen receptor gene expression and growth inhibitory effect of dihydrotestosterone on human adrenocortical cells.

Evidence for the expression of the canonic androgen receptor (AR) in human adrenal cortex has not been provided so far. The aim of the present study was to demonstrate the expression of the AR gene in normal and neoplastic adrenocortical human tissues and in the human adrenocortical cancer cell line, NCI-H295, and then to evaluate the effect of dihydrotestosterone (DHT) on human adrenocortical cell growth. An AR cDNA fragment with the expected size of 262 bp was detected by using reverse transcription (RT)-PCR in normal and neoplastic adrenocortical human tissues and in the neoplastic cell line, demonstrating that the gene for AR is indeed expressed in human adrenal cells. In the human adrenocortical cancer cell line NCI-H295, DHT at physiological concentrations produced a significant reduction in cell proliferation and inhibition of colony formation in soft agar. The inhibitory effect on adrenocortical cell growth was evident after both 24 and 48 h of treatment. The antiandrogens, cyproterone acetate and hydroxyflutamide, were capable of reversing the effects exerted by DHT. The androgen-induced growth inhibitory effect was also detected in primary culture of three non-functioning adrenocortical adenomas. These findings show that the canonic AR is present in human adrenocortical cells and that androgens may have a role in the adrenal cortex by reducing cell proliferation.

5' region and exon 7 mutations of the TP53 gene in two cases of B-cell prolymphocytic leukemia.

We previously found that cases of typical B-chronic lymphocytic leukemia (CLL), atypical B-CLL with t(11;14) and mantle cell lymphomas characterized by rapid progression of the disease and resistance to therapy, had mutations of the TP53 gene. In this paper, abnormalities of the TP53 gene were investigated in two cases of prolymphocytic leukemia, one with t(11;14)(q13;q32), evolving from atypical CLL (patient 1), and one presenting as a de novo condition (patient 2). TP53 DNA was investigated by Southern blot and PCR-SSCP analysis, and TP53 expression was investigated by Northern blot analysis and immunocytochemistry. C-MYC and BCL-1/PRAD1 gene expression were also investigated. Restriction enzyme analysis of TP53 DNA in patient 1 showed alteration of fragments including exon I and intron I, and, in both patients, a specific loss of TP53 DNA. In patient 2, PCR direct sequencing showed in exon VII a 9 bp deletion including codons 252-254. In patient 1, TP53 RNA and protein were not found, indicating that the unusual 5' rearrangement has affected TP53 gene expression. By contrast, patient 2 exhibited detectable TP53 RNA and protein. Detectable but weak BCL-1/PRAD1 RNA was present in both patients, whereas C-MYC RNA expression was clearly present only in case 1. The presence of TP53 hemizygous mutations in both patients suggests that TP53 abnormalities may be important in the pathogenesis of prolymphocytic leukemia (PLL), and may possibly account for the frequent resistance to therapy observed in this disease.

Cytogenetic and interphase cytogenetic characterization of atypical chronic lymphocytic leukemia carrying BCL1 translocation.

Conventional chromosome analysis (CCA) and fluorescent in situ hybridization (FISH) studies, using a 390-kb yeast artificial chromosome probe spanning the area of multiple breakpoints of the BCL1 locus at 11q13, were performed on 57 patients fulfilling the French-American-British criteria for the diagnosis of atypical B-cell chronic lymphocytic leukemia (CLL). To better define the incidence of 13q deletions and trisomy 12, FISH analysis was also performed using a cosmid probe that recognized a DNA sequence between the Rb gene and the D13S25 locus at band 13q14 and a chromosome 12-specific pericentromeric probe. All patients were characterized by cytoimmunological and hematological studies. Fourteen cases displayed three fluorescent signals in 41-98% interphase cells when hybridized to the BCL1 yeast artificial chromosome probe, documenting the presence of BCL1 translocation (BCL1-positive cases). The presence of t(11;14)(q13;q32) was ascertained in 12 cases using CCA and by dual color interphase FISH using the BCLI probe and a 14q telomere probe in 2 karyotypically normal cases. The remaining 43 cases had two signals in more than 95% interphase cells (BCL1-negative) and did not have the t(11;14) at CCA. Although 13q14 deletions were seen by means of CCA in only 5 of 14 BCL1-positive cases, hemizygous or homozygous deletions at band 13q14 were detected by FISH in 11 of 14 BCL1-positive cases, as compared with 17 of 43 BCL1-negative cases (P = 0.01). A subclone with trisomy 12 in addition to BCL1 translocation and del(13q14) was present in four BCL1-positive cases. We arrived at the following conclusions: (a) FISH with this BCL1 YAC probe is an efficient method for the detection of the t(11;14) and of the corresponding involvement of the BCL1 locus in this lymphoproliferative disorder; (b) the majority of BCL1-positive atypical CLLs by French-American-British criteria may carry 13q14 deletions; (c) the recognition of this cytogenetic subset of atypical CLL, sharing some immunological and cytogenetic features with mantle cell lymphoma, may be important, because these patients usually present isolated peripheral blood and marrow lymphocytosis, with or without mild to moderate spleen involvement, and may require early cytotoxic treatment.

Inhibitory effect of dihydrotestosterone on human thyroid cell growth.

Sex steroid-binding activities have been identified by several authors in normal and pathological thyroids and the expression of the canonic androgen receptor (AR) has recently been demonstrated in human thyroid follicular cells. In order to assess what influence, if any, androgen exposure has on thyroid cell growth, the effect of dihydrotestosterone (DHT) on [3H]thymidine (thy) incorporation and cell proliferation was investigated in thyroid follicular cells in vitro. In a primary culture of goitrous cells, DHT induced a significant reduction of [3H]thy incorporation at concentrations ranging from 10(-12) to 10(-8) M, with a more pronounced effect at 10(-9) M. At this concentration, the inhibitory effect was evident after both 24 and 48 h of treatment and in various types of primary thyroid cell cultures. In goitrous cells, the DHT-induced decrease of [3H]thy was associated with a reduction of expression of the proliferation-associated nuclear Ki-67 antigen, a protein commonly used to assess cell growth fraction. In TPC cells, an AR-positive thyroid papillary carcinoma cell line, DHT at concentrations between 10(-12) and 10(-8) M significantly decreased the growth rate. DHT (10(-9) M) produced an approximately 50-60% inhibition of cell proliferation and the antiandrogen cyproterone acetate was capable of reversing such effects. The DHT-induced reduction of TPC cell proliferation was associated with a significant reduction of c-myc RNA levels. Thyroperoxidase mRNA levels and thyroglobulin production were not reduced by androgen in primary cultures of goitrous cells. In conclusion, our results indicated that androgens may have a role in this gland by reducing the proliferation, but not the function, of follicular cells.

Richter's syndrome in a case of atypical chronic lymphocytic leukaemia with the t(11;14)(q13;q32): role for a p53 exon 7 gene mutation.

Clinicobiological, histological, cytogenetic and molecular genetic studies were performed in a case of atypical B-cell chronic lymphocytic leukaemia (B-CLL) with the t(11;14)(q13;q32) evolving into Richter's syndrome (RS) in order (a) to determine the clonal relationship between the cell of origin for B-CLL and RS, and (b) to analyse genetic events underlying the disease progression in this patient. After 4 years following diagnosis, a rapid deterioration of the clinical picture occurred, concomitant with the appearance of large lymphoid blasts in peripheral blood (PB), bone marrow (BM) and ascites samples. A diagnosis of RS was made and cytogenetic analysis revealed karyotype evolution with trisomy 7 and del(17p) in addition to t(11;14). Fluorescence in situ hybridization showed 78% lymphoid blast cells obtained from ascites sample to be trisomic using a chromosome-7-specific pericentromeric probe. Whereas no rearrangement of the c-myc proto-oncogene was detected at disease progression, direct sequencing of p53 gene exon 5-9 revealed an exon 7 missense point mutation. This abnormality was not present in the CLL phase. Immunological staining with the monoclonal antibody PAb-1801, detecting the p53 protein product, revealed a negative pattern in the CLL phase, whereas 24% positivity was documented in representative samples obtained at RS. It is concluded that RS was cytogenetically related with B-CLL in this patient, suggesting the occurrence of a bona fide transformation and that the mutation of p53 exon 7, in association with the development of 17p deletion, possibly played a role in the development of RS.

Atypical chronic lymphocytic leukaemia with t(11;14)(q13;q32): karyotype evolution and prolymphocytic transformation.

In order to define better the cytological and clinical features of atypical B-cell chronic lymphocytic leukaemia (B-CLL) with t(11:14)(q13;q32), sequential morphologic immunological and cytogenetic studies were performed in seven patients belonging to a series of 72 consecutive cases presenting with a diagnosis of CLL or atypical CLL according to the FAB criteria. Cytologic diagnosis in these seven patients with t(11;14) was typical CLL in two cases presenting with < 10% large lymphocytes (LL) and prolymphocytes (PL) and atypical CLL in five cases in which LL and PL comprised between 10% and 55%. The diagnosis was supported by histologic findings on bone marrow biopsy (five cases) or splenectomy specimens (two cases). A progressive increase of peripheral LL and PL was observed, resulting in a switch of FAB diagnosis over a 6-60-month period from typical CLL into atypical CLL in two cases and from atypical CLL into prolymphocytic leukaemia in five cases. Immunophenotyping showed a mature B-cell phenotype with CD19, CD22, CD24 positivity and CD10 negativity in all patients. A bright-staining pattern for surface immunoglobulins (SIg) was detected in 6/7 cases, CD5 positivity in 6/7 cases, and CD23 positivity in 1/7 cases. The FMC-7 monoclonal antibody was positive in > 40% cells in 5/6 cases. Chromosome changes in addition to t(11;14) were seen in five cases; in two cases unbalanced translocations involving the 3q21 chromosome region, resulting in partial trisomy for the long arm of chromosome 3, were detected early in the course of the disease. Karyotype evolution that was associated with disease progression occurred in 3/6 assessable patients. Comparison of these findings with similar data from 65 B-CLL patients without t(11:14) showed that atypical morphology, switch of FAB diagnosis during the course of the disease, and karyotype evolution were more frequently seen in cases with t(11;14) (5/7 v 15/65 cases, P = 0.015, 7/7 v 7/65 cases, P < 0.0001, and 3/6 v 5/45 assessable cases, P = 0.04, respectively). The frequency of positivity for CD23 and bright SIg staining differed significantly in the two groups. It is concluded that t(11;14) identifies a cytologically atypical subset of B-CLL, characterized by frequent cytologic and cytogenetic evolution and by a distinct immunological profile, sharing some biological features with mantle cell lymphoma.

Primary gastric lymphoma: distribution and clinical relevance of different epidemiological factors.

BACKGROUND: Over the last 10 years the incidence of primary gastric lymphomas (PGL), and in particular those of MALT origin, has significantly increased. Recent works correlated this epidemiological observation to Helicobacter pylori (HP) infection. On the other hand, new evidence demonstrating that occupational exposure to pesticides and solvents has played an important role in the pathogenesis of non-Hodgkin lymphomas (NHL) has emerged from studies involving large series of patients. METHODS: Thirty PGL patients, observed between 1986-1992, were subdivided according to HP infection, history of previous gastric disturbances (G) and exposure to pesticides and solvents (T). RESULTS: On the basis of these parameters we divided the patients into three groups: T+HP+ (8), T+HP- (7), T-HP+ (9). T+ patients had a positive history of gastric problems or a positive histological biopsy in 13.3% of cases, versus 66.7% in T- patients. The incidence of HP infection in the T+ group was 53%, which proved to be comparable to the statistics for northeastern Italy, while in the T- group the incidence of infection was 100%. CONCLUSIONS: On the whole these data suggest that HP infection could be considered a pathogenetic factor in 34% of patients, while occupational exposure to pesticides and solvents could have played a more important role in 66% of these cases.

Loss of heterozygosity in ovarian cancer: detection by PCR and microsatellite polymorphism.

Loss of chromosome 6q was investigated in endometrial and ovarian carcinomas by a PCR based-microsatellite polymorphism analysis. Results obtained show that this technique is able to detect frequent loss of heterozygosity in the ovarian cancers (10/27) and only in the serous type (8/17). Then, this kind of analysis can contribute to the understanding of tumor development and progression of ovarian cancers with different histopathological features.

Androgen responsiveness and androgen receptor gene expression in human kidney cells in continuous culture.

The effects of androgen and estrogen on cell growth and gene expression were investigated in KJ29 kidney epithelial cells. Incorporation of 3H leucine and 3H thymidine was increased by androgen at 10nM, but not by estrogen. Estrogen however, inhibited the effects induced by androgen. In addition, cell number and the proliferation marker Ki67 were increased by androgen, but not by estrogen. Levels of androgen receptor RNA, as detected by RT-PCR and Northern blot analysis, were not affected by either androgen or estrogen. Levels of estrogen receptor RNA could be detected only by RT-PCR, and disappeared after estrogen treatment. These studies show that sex steroid receptors are differently expressed in KJ29 cells, and suggest that androgen, via its canonic receptor, acts as a mitogenic factor in human kidney cells, whereas estrogen has an antiandrogenic action.

Lymphoblastic lymphoma with primary splenic involvement and the classic 14;18 translocation.

Clinicopathologic features of a case of lymphoblastic lymphoma (LyL) with the classic 14;18 translocation are described in this article. The patient had prominent splenomegaly with numerous splenic nodules, exhibiting a homogeneous blast cell infiltrate and occasional cells with cleft nuclei, a picture suggestive of high-grade non-Hodgkin lymphoma (NHL) possibly lymphoblastic. Early B-cell features were detected immunologically, thus confirming the diagnosis of LyL. The presence of primary splenic involvement and of the t(14;18)(q32;q21) are unusual in this histologic subset of B-cell NHL, these cytogenetic and clinicopathologic characteristics being typically associated with low- or intermediate-grade NHL of follicle center origin. These features, along with the presence of some centrocytelike cells in the biopsy sections, suggest that an unusual pattern of histologic evolution from a follicle center cell NHL may have occurred in this case of LyL.

Henoch-Schönlein purpura after Salmonella hirschfeldii infection.

The authors present a case of Henoch-Schönlein purpura in a young soldier (19 years old) which they consider important for its etiology and the length of its oligoanuric phase. The syndrome followed a Salmonella hirschfeldii infection, and a protracted oligoanuric phase was followed by nephrotic syndrome and selective glomerular proteinuria which lasted for 1 year. The young man recovered after the eradication of the Salmonella. It seems possible that there was an overall anomalous regulation of the 'lymphoid system of the mucosa', perhaps dependent on a genetic predisposition.

Radiological features of dialysis amyloid spondyloarthropathy.

Nine patients undergoing regular dialytic treatment (RDT) for more than 60 months (mean 125 +/- 33 months) showed clinical and radiological evidence of non-infective destructive spondyloarthropathy (DSA). The cervical spine was the skeletal segment most affected (100% of cases). Three patients were found also to be suffering from discal and bone alterations of the dorsal column, and in two other patients the vertebral bodies L4-L5 were changed. Typical radiological pictures showed a narrowing of intervertebral spaces with the destruction or sclerosis of adjacent subchondral bones, erosions of vertebral body plates and cavitations. CT studies of the altered spines confirmed discal lesions and osteolytic areas with bone condensation at each level. Ligamentous lesions resulting in severe disorders of spinal statics were discovered during autopsy of three patients. Histological study of disc and peridiscal ligaments indicated the presence of large amyloid deposits containing beta-2-microglobulin (B2-m). It is possible that the minor biocompatibility of the cuprophan membrane of dialyzers is the most significant factor responsible for the hyperproduction of B2-m and thus of the osteo-articular deposition of a new type of amyloidosis.