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Angiosarcoma (AS) is the most frequent primary sarcoma of the breast but nevertheless remains uncommon, accounting for <0.05% of breast malignancies. Secondary mammary AS arise following radiation therapy for breast cancer, in contrast to primary AS which occur sporadically. Essentially all show aggressive clinical behavior independent of histologic grade and most are treated by mastectomy. MYCamplification is frequently identified in radiation-induced AS but only rarely in primary mammary AS (PMAS). As a heterogeneous group, AS from various anatomic sites have been shown to harbor recurrent alterations in TP53, MAP kinase pathway genes, and genes involved in angiogenic signaling including KDR(VEGFR2) and PTPRB. In part due to its rarity, the pathogenesis of PMAS has not been fully characterized. In this study, we examined the clinical, pathologic, and genomic features of ten cases of PMAS, including one patient with bilateral disease. Recurrent genomic alterations were identified in KDR(70%), PIK3CA/PIK3R1(70%), and PTPRB(30%), each at higher frequencies than reported in AS across all sites. Six tumors harbored a KDRp.T771R hotspot mutation, and all seven KDR-mutant cases showed evidence suggestive of biallelism (four with loss of heterozygosity and three with two aberrations). Of the seven tumors with PI3K alterations, six harbored pathogenic mutations other than in the canonical PIK3CAresidues which are most frequent in breast cancer. Three AS were hypermutated (≥10 mutations/megabase (Mb)); hypermutation was seen concurrent with KDRor PIK3CAmutations. The patient with bilateral disease demonstrated shared alterations, indicative of contralateral metastasis. No MYCor TP53aberrations were detected in this series. Immunohistochemistry for VEGFR2 was unable to discriminate between KDR-mutant tumors and benign vascular lesions of the breast. These findings highlight the underrecognized frequency of KDRand PIK3CAmutation in PMAS, and a significant subset with hypermutation, suggesting a pathogenesis distinct from other AS.

Angiosarcoma (AS) is the most frequent primary sarcoma of the breast but nevertheless remains uncommon, accounting for <0.05% of breast malignancies. Secondary mammary AS arise following radiation therapy for breast cancer, in contrast to primary AS which occur sporadically. Essentially all show aggressive clinical behavior independent of histologic grade and most are treated by mastectomy. MYCamplification is frequently identified in radiation-induced AS but only rarely in primary mammary AS (PMAS). As a heterogeneous group, AS from various anatomic sites have been shown to harbor recurrent alterations in TP53, MAP kinase pathway genes, and genes involved in angiogenic signaling including KDR(VEGFR2) and PTPRB. In part due to its rarity, the pathogenesis of PMAS has not been fully characterized. In this study, we examined the clinical, pathologic, and genomic features of ten cases of PMAS, including one patient with bilateral disease. Recurrent genomic alterations were identified in KDR(70%), PIK3CA/PIK3R1(70%), and PTPRB(30%), each at higher frequencies than reported in AS across all sites. Six tumors harbored a KDRp.T771R hotspot mutation, and all seven KDR-mutant cases showed evidence suggestive of biallelism (four with loss of heterozygosity and three with two aberrations). Of the seven tumors with PI3K alterations, six harbored pathogenic mutations other than in the canonical PIK3CAresidues which are most frequent in breast cancer. Three AS were hypermutated (≥10 mutations/megabase (Mb)); hypermutation was seen concurrent with KDRor PIK3CAmutations. The patient with bilateral disease demonstrated shared alterations, indicative of contralateral metastasis. No MYCor TP53aberrations were detected in this series. Immunohistochemistry for VEGFR2 was unable to discriminate between KDR-mutant tumors and benign vascular lesions of the breast. These findings highlight the underrecognized frequency of KDRand PIK3CAmutation in PMAS, and a significant subset with hypermutation, suggesting a pathogenesis distinct from other AS.

Immunoglobulin A (IgA) vasculitis or Henoch-Schönlein purpura (HSP) typically occurs in the pediatric population, although rare cases also occur in adults. Gastrointestinal (GI) involvement is common. The “classic” histologic finding in IgA vasculitis (HSP) is leukocytoclastic vasculitis (LCV); other histologic features in biopsies of IgA vasculitis (HSP) have only been rarely described. The pathology archival files at our institution were searched for GI biopsies from patients with IgA vasculitis (HSP). Slides were retrieved and histologic and clinical features were reviewed. We identified 16 patients with IgA vasculitis (HSP) with a GI biopsy series, including both adult and pediatric patients. The most common histologic abnormality was lamina propria hemorrhage (all cases) with many cases also showing lamina propria fibrin deposition with red cell sludging and nuclear debris (7 cases). Twelve of the 16 duodenal biopsies had acute duodenitis; 3 of which were severe and erosive. Several also had an eosinophilic infiltrate. Seven of the 9 jejunal and/or ileal biopsies had acute jejunitis or ileitis. An acute colitis or proctitis was observed in 9/12 colorectal biopsies. Four biopsies contained LCV; in each of these cases, the involved vessels were small capillaries within the lamina propria. Only 1 biopsy contained deeper submucosal vessels, but they were uninvolved. Sites involved by LCV included the colorectum (2 cases), colorectum and terminal ileum, terminal ileum only, duodenum, and jejunum (1 case each). All patients presented with abdominal pain; 13/16 developed a rash, 1 following the index biopsy. Other presenting symptoms included diarrhea and/or hematochezia (8 cases), nausea/vomiting (5 cases), and intussusception (1 case). Four patients had concurrent skin biopsies showing LCV; only 1 of these patients had LCV on GI biopsy. Indications for biopsy included nonspecific presenting symptoms, absence of rash at presentation, and/or failure to respond adequately to steroid therapy. Biopsies are commonly performed in patients with or without suspected IgA vasculitis (HSP) to rule out infection, inflammatory bowel disease, and less commonly, vasculitis. In general, vasculitis is not commonly observed in GI biopsies of patients with IgA vasculitis (HSP), and the spectrum of findings includes neutrophilic infiltrate within the small bowel and colon, with the duodenum most commonly affected. While the clinical and histologic findings may mimic early inflammatory bowel disease, the presence of predominant small bowel involvement, especially erosive duodenitis, should raise suspicion for IgA vasculitis (HSP). Biopsies should be obtained before steroid therapy is initiated, if possible.

Adenoviruses are common pathogens that usually cause self-limited infections. However, in the immunocompromised host they can cause severe infections involving multiple organs including the liver. A search of the pathology database at Stanford University Medical Center (1995 to 2016) identified 12 cases of adenovirus hepatitis including biopsy and autopsy specimens. There were 8 pediatric patients, 7 of which had received orthotropic liver transplants and 1 of which was receiving chemotherapy for lymphoblastic leukemia. There were 4 adult patients, of which 1 was actively receiving chemotherapy for chronic lymphocytic leukemia and 2 had undergone hematopoietic stem cell transplantation for hematologic malignancies. One patient had lymphoplasmacytic lymphoma and had received chemotherapy over a year prior but was not receiving therapy at the time he contracted adenovirus hepatitis. In all cases, histologic sections showed nonzonal coagulative hepatocyte necrosis and characteristic intranuclear inclusions. Hepatocyte necrosis ranged from spotty to massive. The majority of cases (7/12; 58%) had no associated inflammation. If present, inflammation was focal and lymphohistiocytic. In 1 case, findings were focal within the liver, requiring an image-guided biopsy. This patient underwent a simultaneous nontargeted liver biopsy that lacked histologic evidence of adenovirus. Among the pediatric patients, 63% (5/8) died secondary to organ failure, while there was 100% (4/4) mortality in the adult population.

The 2013 CAP/ASCO HER2 Testing Guidelines Update modified HER2 FISH categories such that some cases with ‘monosomy’, ‘co-amplification/polysomy’, low-level increased HER2 signals or clustered heterogeneity now are considered amplified or equivocal. This study examines the frequency and clinico-pathologic characteristics of breast cancers with equivocal or ‘non-classical’ HER2 FISH results. Breast cancers (2001–2014) with HER2 FISH results, HER2 immunohistochemistry, ER, grade, and age from three institutions (Stanford, UCSF, UWMC) were collected. HER2 FISH was interpreted using the updated recommendations. Amplified cases with non-classical results were grouped into the following categories: (1) ‘monosomy’ (ratio ≥2.0, mean HER2/cell<4.0); (2) ‘co-amplified’ (ratio<2.0, mean HER2/cell ≥6.0); (3) ‘low amplified’ (ratio ≥2.0, mean HER2/cell 4.0–5.9). Heterogeneous cases with clustered HER2-positive cells were also included. Of 8068 cases, 5.2% were equivocal and 4.6% had a ‘non-classical’ HER2 amplified result; 1.4% ‘monosomy’, 0.8% ‘co-amplified’, 2.1% ‘low amplified’, and 0.3% clustered heterogeneity. These cancers had a high frequency of ER positive (80.4%), Nottingham grade 3 (52.1%) results. The highest percentage of grade 3 cancers (66.7%) and positive HER2 immunohistochemistry (31.7%) was in the ‘co-amplified’ group. The ‘monosomy’ group had the highest percent grade 1 cancers (13.3%) and was most frequently HER2 immunohistochemistry negative (30.1%). Equivocal cases had very similar characteristics to the ‘low-amplified’ category. Cases with non-classical HER2 amplification or equivocal results are typically ER positive, higher grade cancers. ‘Co-amplified’ cases have the highest frequencies of aggressive characteristics and ‘monosomy’ cases the highest frequencies of lower risk features. With little clinical outcomes data currently available on these non-classical HER2 results, these results support the current classification scheme for HER2 FISH, with case-by-case correlation with additional clinical-pathologic factors when evaluating whether to offer HER2-targeted therapies in these non-classical cases.

The 2013 CAP/ASCO HER2 Testing Guidelines Update modified HER2 FISH categories such that some cases with ‘monosomy’, ‘co-amplification/polysomy’, low-level increased HER2 signals or clustered heterogeneity now are considered amplified or equivocal. This study examines the frequency and clinico-pathologic characteristics of breast cancers with equivocal or ‘non-classical’ HER2 FISH results. Breast cancers (2001–2014) with HER2 FISH results, HER2 immunohistochemistry, ER, grade, and age from three institutions (Stanford, UCSF, UWMC) were collected. HER2 FISH was interpreted using the updated recommendations. Amplified cases with non-classical results were grouped into the following categories: (1) ‘monosomy’ (ratio ≥2.0, mean HER2/cell<4.0); (2) ‘co-amplified’ (ratio<2.0, mean HER2/cell ≥6.0); (3) ‘low amplified’ (ratio ≥2.0, mean HER2/cell 4.0–5.9). Heterogeneous cases with clustered HER2-positive cells were also included. Of 8068 cases, 5.2% were equivocal and 4.6% had a ‘non-classical’ HER2 amplified result; 1.4% ‘monosomy', 0.8% ‘co-amplified', 2.1% ‘low amplified’, and 0.3% clustered heterogeneity. These cancers had a high frequency of ER positive (80.4%), Nottingham grade 3 (52.1%) results. The highest percentage of grade 3 cancers (66.7%) and positive HER2 immunohistochemistry (31.7%) was in the ‘co-amplified’ group. The ‘monosomy’ group had the highest percent grade 1 cancers (13.3%) and was most frequently HER2 immunohistochemistry negative (30.1%). Equivocal cases had very similar characteristics to the ‘low-amplified’ category. Cases with non-classical HER2 amplification or equivocal results are typically ER positive, higher grade cancers. ‘Co-amplified’ cases have the highest frequencies of aggressive characteristics and ‘monosomy’ cases the highest frequencies of lower risk features. With little clinical outcomes data currently available on these non-classical HER2 results, these results support the current classification scheme for HER2 FISH, with case-by-case correlation with additional clinical-pathologic factors when evaluating whether to offer HER2-targeted therapies in these non-classical cases.

We report the case of a 53-year-old woman with Sjögren syndrome and cryoglobulinemia. The patient presented with nephrotic syndrome, hematuria, and reduced estimated glomerular filtration rate. The kidney biopsy revealed diffuse endocapillary proliferation and leukocyte exudation with focal intraluminal hyaline thrombi, prominent tubulointerstitial inflammation, and vasculitis. Diffuse granular mesangial and segmental to global capillary wall staining was observed on immunofluorescence with antisera to C3 and immunoglobulin M (IgM), with less intense staining indicative of IgG and κ and λ light chains. A biopsy diagnosis of Sjögren syndrome–related cryoglobulinemic membranoproliferative glomerulonephritis and vasculitis was rendered. Subsequent investigations revealed the presence of circulating type II cryoglobulins with cryocrit of 9%. Although rare, Sjögren syndrome is the most common cause of non–hepatitis C virus–related mixed cryoglobulinemia. We discuss the possible pathogenic mechanisms involved in the development of mixed cryoglobulinemia and its evolution to lymphoma, as best described in the setting of hepatitis C virus infection. Although the specific antigen involved is unknown, it is likely that the mixed cryoglobulinemia in Sjögren syndrome is triggered by the long-term B-cell stimulation, resulting in clonal proliferation of B cells. Additional chromosomal aberrations and cytokine milieu alterations, as seen in hepatitis C virus infection, may result in prolonged B-cell survival and progression to non-Hodgkin lymphoma.

Tamm-Horsfall protein (THP) is a glycoprotein produced only in the thick ascending limb of the loop of Henle. Its primary physiological function is unknown, but it may have a role in host defense against infectious organisms. THP is the primary scaffolding protein in all varieties of tubular casts. Under certain conditions, THP may be extruded from tubular lumens into the interstitium and lymphatic channels. It even may be found within lymph nodes sampled for staging of neoplastic conditions. THP deposits were described in lumens of large veins. The pathogenetic basis of this finding is not known, but obstruction of renal outflow was suggested, and several cases were associated with macroscopic hematuria. We report a case of intravenous THP polyposis in which, in addition to abundant hemorrhage, there was formation of a hematoma. This measured 12 cm in diameter and caused clinical concern for the possibility of renal cell carcinoma. Although the cause of the hematoma was not apparent, the association with striking intravenous polyps of THP is noteworthy because this represents the first association of intravenous THP polyps with a large intraparenchymal hematoma.

Nephrocalcinosis most commonly manifests as renal calculi or deposition within the tubulointerstitial compartment. Conversely, calcium deposition within glomeruli is extremely rare. We present the case of a 50-year-old man with multiple medical problems, including hepatitis C, diabetes, hypertension, proteinuria, and chronic renal failure. Renal biopsy showed impressive calcium deposits along glomerular basement membranes and tubular basement membranes, within intracellular organelles, and in the interstitium in the setting of a normal serum calcium level. Seven months after biopsy, the patient is on hemodialysis therapy. Although serological and medical examination failed to show a treatable cause for this patient’s glomerular calcinosis, individual case reports in the literature have described resolution of calcinosis-associated nephrotic syndrome with treatment of the primary cause of hypercalcemia.

Although pulse methylprednisolone therapy (PMT) has been used successfully in the management of children with steroid-resistant nephrotic syndrome (SRNS), the relationship between initial presenting findings and renal histological characteristics to the subsequent clinical response to PMT is unknown. A retrospective analysis was conducted in a study cohort of 42 children (30 boys, 12 girls; mean age, 7.4 ± 4.7 years) with SRNS administered PMT between June 1976 and July 1994 at Stanford University (Stanford, CA). Four diagnostic categories were created: group I, minimal change disease with or without mesangial hypercellularity (n = 10); group II, mesangial proliferation (n = 7); group III, focal segmental glomerulosclerosis (FSGS) with or without mesangial hypercellularity (n = 10); and group IV, FSGS plus mesangial proliferation (n = 15). Primary variables analyzed were remission in response to PMT with or without alkylating agent therapy and end-stage renal disease (ESRD). Remission rates were best in group I (90%) and worst in group IV (46%). With the exception of hematuria, presenting clinical features did not correlate with outcome. Segmental sclerosis, glomerular adhesion to Bowman's capsule, epithelial sloughing, corona (segmental scar surrounded by visceral epithelial cells), subepithelial deposits, inflammatory cells, and percentage of interstitium, immunoglobulin M (IgM), IgG, and C3 deposition univariately correlated with ESRD in univariate analysis. In a multivariate logistic regression model, only segmental sclerosis (P= 0.008) correlated with ESRD. Histological analysis is important because it identifies features, including segmental sclerosis, that portend a poor prognosis in children with SRNS. © 2002 by the National Kidney Foundation, Inc.

To describe the long-term survival, renal condition, and morbidity outcomes in patients who received total lymphoid irradiation (TLI) for the treatment of lupus nephritis. Twenty-one patients with biopsy-proven, diffuse membranoproliferative glomerulonephritis and significant proteinuria of >2.5 grams/day received TLI from 1980 to 1987 at Stanford University Medical Center. All patients had previously failed to respond to treatment with high-dose corticosteroids or therapy with corticosteroids plus immunosuppressive agents (azathioprine, cyclophosphamide, or chlorambucil). The mean duration of followup since TLI was 10.7 years. Fifteen of 21 patients (71%) remained alive at the time of this assessment. Nine of the 21 patients (43%) survived without developing end-stage renal disease (ESRD). The probability of long-term survival without ESRD and without need for additional immunosuppressive agents after TLI was 19% (4 of 21). Factors predicting renal failure at the time of TLI included elevated creatinine levels, increased interstitial fibrosis on renal biopsy, and increased fractional excretion of immunoglobulin and albumin. Malignancies were found in 4 patients, and opportunistic infections occurred in 7 patients. Overall, patients with lupus nephritis treated with TLI do not appear to have better 10-year survival with lower incidence of ESRD compared with patients in published series treated with conventional immunosuppressive therapies. However, in this series of patients, treatment with conventional immunosuppressive therapies had been unsuccessful and given the limited number of adverse events and the efficacy seen in some patients, TLI appears to be a reasonable therapeutic option for the treatment of severe lupus nephritis among patients who fail to respond under standard cytotoxic regimens.

Previous studies have shown that posttransplant total lymphoid irradiation, anti-thymocyte globulin, and an intravenous donor blood cell infusion induce tolerance to ACI heart allografts in Lewis rat hosts.

Fetal pancreas (FP) has the capacity for abundant proliferation and beta cell differentiation. Insulin-like growth factor-1 (IGF-1) promotes FP engraftment in the i.m. site and reversal of diabetes in a rodent model. However, reversal of diabetes by an FP transplant in rats under the influence of IGF-1 is still an inefficient process requiring multiple FP grafts and a prolonged latent period. Numerous other growth and differentiation factors, which include platelet derived growth factor (PDGF), vascular endothelial growth factor, endothelial cell growth factor-alpha and pancreatic islet neogenesis-associated protein, have been implicated in beta cell neogenesis and proliferation. We have analyzed the in vivo role of these growth factors in FP engraftment and reversal of streptozotocin-induced diabetes in rats.

Previous studies showed that an intravenous infusion of donor blood cells facilitates tolerance to ACI heart allografts in Lewis rat hosts given posttransplant total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG). The object of the current study was to compare tolerance induction using donor cells that do or do not induce chimerism.

The outcome of renal transplantation in patients with hemolytic-uremic syndrome (HUS) is variable in reported cases. An update of the previously published series of patients from the University of Minnesota is reported. Seventeen patients with HUS received a renal transplant. Seven patients had recurrent HUS based on strict clinical and histological features and in 4 of these patients grafts were loss from recurrent HUS, with 1 patient losing three successive grafts. Three patients had histological features consistent with HUS but lacked some of the clinical features. Seven patients had no evidence of recurrent HUS post transplantation. The incidence of recurrence of HUS post transplantation in this updated report remains high (7/17 patients). There was no difference in the allografts used (living-related donor grafts were more common in all groups) or in the immunosuppression in the different groups of patients; only 1 patient with recurrent HUS received cyclosporine. The published cases of transplantation in patients with HUS show a variable recurrence rate of 0–25% in different centers with a poor graft outcome in patients with recurrence; a higher incidence of early chronic vascular rejection with decreased graft survival is also reported in patients without recurrence. Patients with HUS post renal transplant are at a variable risk of recurrence of HUS or decreased graft survival, and the factors responsible for this outcome are not known.

We were concerned that clinical manifestations of rejection (R) might be subtle in small children transplanted with adult kidneys. We retrospectively analyzed the first rejection episode (biopsy proven) in 22 children (R group) under age 4 years [mean age, 23.7±2.2 months (±SEM); mean weight, 9.4±0.4 kg] receiving an adult-related donor kidney. We matched these patients for age, date of transplant, donor source and immunosuppression with 36 children without R (control or C group). We compared both groups at similar intervals from transplantation, based on the time of R (5.38±1.2 months) in the R group and analyzed the immediate 8-week period prior to R and the corresponding interval in the C group. Hypertension occurred in 82% (18/22) of the R versus 8% (3/36) of the C group (P<0.01). Fever longer than 7 days occurred in 45% (10/22) of the R versus 0% (0/36) of the C group (P<0.01). Increased creatinine occurred in only 45% (10/22) of the R versus 3% (1/30) of the C group (P<0.01). Cyclosporine did not influence these manifestations of R. The clinical manifestations did not predict the R grades on biopsy, which were moderate to severe in 13 and mild in 9 of the R patients. Graft survival was higher at 3 years in the C (95%) than in the R patients (65%), (P<0.004). Thus, clinical manifestations of acute R can be subtle in small children with adult renal allografts. Renal biopsy should not be delayed until the creatinine is elevated in these patients.

RANTES is a member of a large family of cytokines, called chemokines, which are thought to play a regulatory role in inflammatory processes. We have made recombinant human RANTES protein which was used to generate a panel of anti-RANTES monoclonal antibodies. Following characterization, select anti-RANTES monoclonal antibodies were used for immunohistologic staining of a large panel of normal, diseased and fetal tissue sections. Diseased tissues included eleven lymphomas and eight renal tumors. Most tissues were also tested in parallel for RANTES mRNA by in situ hybridization using RANTES mRNA specific oligomeric probes. As expected, most normal adult tissues contain few, if any, RANTES positive cells. In constrast, RANTES expression dramatically increases in inflammatory sites. In addition, megakaryocytes, some tumours, and select fetal tissues express high levels of RANTES message and protein. These results indicate a wider expression of RANTES than previously appreciated and suggest multiple physiologic roles for this soluble factor.

Nitric oxide (NO) is a ubiquitous molecule that has been associated with inflammation, arthritis, autoimmune disease, bone resorption, and other biological processes. Elucidating the role of NO at the bone–implant interface may further our understanding of the biological processes of osseointegration, loosening, and osteolysis. This study demonstrates the use of a molecular biological technique to investigate the possible role of NO in prosthetic loosening and periprosthetic bone resorption following total hip arthroplasty. Periprosthetic tissue from 12 patients undergoing revision hip arthroplasty was harvested and total ribonucleic acid (RNA) was extracted. In six of the 12 patients, multiple samples from different anatomic locations along the same interface were studied. To estimate the amount of NO present in the tissues in vivo, the level of inducible NO synthase (iNOS) messenger RNA (mRNA) was determined using a ribonuclease (RNase) protection assay. Inducible NOS mRNA was detected in every tissue sample; there was no correlation between iNOS mRNA levels and clinical loosening or osteolysis. Analysis of multiple tissue samples from the same prosthetic component revealed that the levels of iNOS mRNA vary greatly, confirming the heterogeneous nature of the interface. © 1998 John Wiley & Sons, Inc. J Biomed Mater Res, 40, 419–424, 1998.

Cytokines have been implicated as pivotal mediators of the woundhealing process. An understanding of the production and interaction of cytokines may lead to a better appreciation of the complex mechanisms of flap ischemia. The potential would then exist for novel diagnostic and therapeutic approaches to prevent and reverse damage to the endangered flap.

We studied human prostatic specific antigen (PSA) localization in human prostate to investigate the possibility that the previously reported variations in the intensity of antigen staining were due to fixation and embedding methods. We have evaluated the effects of physical and several chemical fixatives on prostate samples obtained immediately after prostatectomies and radical cystectomies. Our analysis of fixation effects and immunohistochemical staining of polyclonal antibody to PSA indicates that the formalin fixation and paraffin embedding methods used previously did provide optimum localization of the antigen and the variations in the intensity of PSA staining could not be attributed to the methodology. Although PSA staining was relatively uniform in the lower grade neoplastic tumors, the higher grade, moderately to poorly differentiated tumors showed intense-through-weak PSA localization or no PSA staining suggesting that PSA staining intensity was not uniformly related to tumor differentiation.

We evaluated a combined posttransplant strategy using antilymphocyte serum (ALS) at time of engraftment followed by low dose total lymphoid irradiation (TLI) and donor bone marrow cell (BMC) inoculation administered either intrathymically (IT) or intravenously (IV) in the vigorously rejecting strain combination DA into Lew recipients. Allograft survival was significantly prolonged with administration of ALS in combination with TLI and IT (105 ± 28.6 days) or IV (106.8 ± 28.6 days) BMC compared to administration of ALS combined with either TLI (17.8 ± 0.4 days) or BMC (9.0 ± 0.0 days), or TLI combined with BMC (11.5 ± 0.5 days) (P< 0.0001, experimental vs control animals). There was no difference in survival between those animals who underwent IT or IV BMC inoculation. Third-party (WF) BMC inoculation did not significantly prolong allograft survival (10.0 ± 1.0 days). A mild to moderate cellular infiltrate was present in allograft tissue after 100 days. To further characterize these cells, cytokine mRNA expression in allograft tissue (>100 days posttransplant) was evaluated using nonisotopic in situ hybridization. A similar cytokine profile was demonstrated in allograft tissue compared to naive and isograft tissue, except for a slight increase in IL-2 (P< 0.02, control vs IV BMC;P= NS, other groups). In summary, unresponsiveness was induced in a high-responder strain combination using a combined posttransplant strategy of ALS, TLI, and donor antigen either IT or IV. The cytokine profile of the graft infiltrating cells was similar to that of normal tissue. Unresponsiveness may be the result of functional inactivation of these cells.

Homozygous adenine phosphoribosyltransferase deficiency is a genetic defect that is associated with 2,8-dihydroxyadenine urolithiasis. Since the prevalence of the heterozygous state is found in 0.4% to 1.2% of the population, it is surprising that more cases of 2,8-dihydroxyadenine urolithiasis have not been reported. Herein we describe a patient with complete adenine phosphoribosyltransferase deficiency with 2,8-dihydroxyadenine urolithiasis leading to chronic renal failure. Gene sequencing revealed that the patient is a compound heterozygote. One of the mutations (a T insertion between bases 346 and 347) has been encountered before, but the second (a G-to-A substitution at base 1356) has not been previously reported. Possible explanations for the unexpected rarity of 2,8-dihydroxyadenine urolithiasis are discussed.(Arch Intern Med. 1993;153:767-770)

A 72-year-old female with ulcerative colitis of 30 years duration underwent total proctocolectomy for a cecal mass thought to be an adenocarcinoma. Pathologic examination of the colon revealed 22 tumors, all of which proved to be malignant lymphoma, histiocytic type. Thirteen cases of non-Hodgkins malignant lymphoma and 2 cases of Hodgkins disease of the colon arising in ulcerative colitis are reviewed and discussed.

Renal insufficiency occurs in at least 1.5% of children with anaphylactoid purpura (AP). We reviewed the records of 16 children who developed end-stage renal disease (ESRD group) secondary to AP and matched them for age, era of onset, renal histology, and clinical severity at onset with 16 children who has AP but whose creatinine clearance returned to and remained normal (recovery group). We reviewed creatinine clearances at 1, 3, 5, and 10 years after onset. A creatinine clearance >70 ml/min per 1.73 m2 was present in 50% of the patients in the ESRD group at 3 years and in 25% at 5 years after onset. In contrast, all patients in the recovery group had a creatinine clearance >70 ml/min per 1.73 m2 by 3 years (7 of 16 had a creatinine clearance >125 ml/min per 1.73 m2) and all were normal 95–125 ml/min per 1.73 m2) by 5 years. Thus, the presence of an increased creatinine clearance (>125 ml/min per 1.73 m2) at 3 years predicted recovery, while failure to reach a creatinine clearance of >70 ml/min per 1.73 m2 at 3 years predicted progression to ESRD. There was no evidence of recurrent systemic AP or nephritis in the 14 patients who underwent renal allograft transplantation. We conclude that long-term evaluation of patients over many years is required to identify those who will progress to ESRD from AP and that recurrence of AP in the renal transplant is uncommon.

Immunohistochemistry and in situ hybridization with a synthetic oligonucleotide probe were used to compare the topographical distribution of BCL-2 proto-oncogenic protein with that of its messenger RNA (mRNA) in normal lymphoid tissues, follicular lymphomas, and lymphoma-derived cell lines. In normal lymph nodes, BCL-2 protein was most abundant in the small lymphocytes of primary lymphoid follicles and the mantle zones of secondary follicles, virtually absent within germinal centers, and of variable abundance in many interfollicular cells. In contrast, the distribution of BCL-2 mRNA was roughly reciprocal to that of the protein with intense hybridization signal in germinal centers and almost none in mantle zones. Discordant BCL-2 RNA and protein levels were also observed in tonsillar epithelial cells and cortical thymocytes. Concordant and abundant expression of BCL-2 mRNA and protein was detected in biopsy tissues and cell lines from t(14;18)-carrying lymphomas. The contrasting distributions of BCL-2 protein and RNA in normal lymphoid tissues suggest that translational and posttranslational control mechanisms play a significant role in regulating BCL-2 protein levels in germinal center cells, epithelial cells, and cortical thymocytes. Concordant BCL-2 mRNA and protein levels in follicular lymphomas suggest that translational control mechanisms may be disrupted as part of the sequence of genetic changes that transforms normal lymphoid cells into neoplastic follicular lymphoma cells.

Previous studies showed that a combination of posttransplant total lymphoid irradiation (TLI), rabbit antithymocyte globulin (ATG), and a single donor blood transfusion induced tolerance to ACI heart allografts in Lewis rats. All three modalities were required to achieve tolerance. The objective of the current study was to determine the subset(s) of cells in the donor blood that facilitated long-term allograft survival.

Physiologic and morphologic techniques were used to study kidneys of cardiac transplant recipients treated with either low-dose (low-CsA) or high-dose (high-CsA) cyclosporine. After 12 months both low-CsA (4.6±0.4) and high-CsA (6.3±0.3 mg/Kg/24 hr, p<0.01) were associated with azotemia and hypertension; GFR with each regimen was depressed below values in a third group treated without CsA (no-CsA) by 40–47, while corresponding renal vascular resistance was elevated > 2-fold (P<0.01). Morphologic changes in both CsA groups included an obliterative arteriolopathy with downstream collapse or sclerosis of glomeruli. Determination of renal arcuate vein occlusion pressure revealed an increasing renal artery-to-peritubular capillary pressure gradient between 1 and 12 months of CsA therapy. Fractional clearances of dextrans of graded size were elevated at each time compared with the no-CsA group. Analysis of dextran transport with an isoporous membrane model indicates that transglomerular hydraulic pressure difference (AP) approximated 39 with no-CsA, but was reduced with low-CsA therapy to about 30 at 1 month, and about 34 mmHg after 12 months. We conclude that chronic CsA therapy induces constriction and eventual occlusion of afferent arterioles, causing downstream glomerular damage that is irreversible. Low versus high dosage of CsA confers only marginal protection against this serious microvascular injury.

Renal transplantation was performed in 25 patients for renal failure secondary to nephrotic syndrome and histologically proven focal segmental glomerulosclerosis (FSGS). They received 33 allografts, 13 from cadaveric (CAD) and 20 from living related donors (LRD) including 6 HLA-identical siblings. All have been followed for at least 1 year with none lost to follow-up. Overall, functional graft survival of the 33 grafts was 68.7 at 12 months and 60.5 at 48 months, similar to controls matched for age, sex, time of transplant, and donor source. Recurrent FSGS was documented histologically in 9 (5 CAD and 4 LRD) of 33 grafts (27.3) and resulted in loss of graft function in 3 (9.9). The presence and extent of mesangial proliferation (MP) in conjunction with or preceding typical lesions of FSGS in native kidneys was predictive of recurrent disease. Age at onset, duration of disease, and donor source were not. Sixteen patients with only FSGS on multiple biopsies of native kidneys received 22 allografts and recurrent disease occurred in 4 (18) but did not cause loss of graft function in any. Six patients with focal areas of MP as well as FSGS underwent eight transplants, in which recurrent FSGS developed in two (25) and caused graft loss in one. All three grafts transplanted to the patients with diffuse MP and FSGS developed recurrent disease, this resulting in graft failure in two. This study demonstrates the importance of a thorough histological evaluation by multiple biopsies of all patients with steroid-nonresponsive nephrotic syndrome. Only in this manner does it appear possible to define that subgroup of patients with FSGS who are at greatest risk of clinically significant recurrent disease.

A 2½-year-old female with a sphenooccipital-vertebral chordoma presented with neck pain, torticollis, fever, a lytic lesion of C2 vertebra, and bilateral nodular infiltrates in the lung. The lung biopsy revealed multiple tumor emboli by an enigmatic epithelioid-appearing neoplasm with immunohistochemical staining for vimentin, cytokeratin, and epithelial membrane antigen. A thorough roentgenographic evaluation disclosed a destructive, prepontine mass in the region of the clivus, erosion of the odontoid process, and compression of the cervical spinal cord. The patient died after a clinical course of 3 months. We identified 16 additional cases of metastasizing chordomas in the pediatric-age population; this case is the first to our knowledge with pathologically documented pulmonary metastasis at presentation.

Cytokines are short-acting protein modulators of many physiologic processes including graft rejection. An understanding of the production, action, and interaction of cytokines may lead to better appreciation of the complex mechanism of graft rejection. The potential would then exist for more selective and less-toxic means of modulating the immune response. A rat hind limb allograft model with major immunohistoincompatibility was used to study the local mRNA expression of IL-1α, IL-2, IL-6, gamma interferon (γINF), platelet-derived growth factor–α (PDGF-α), basic fibroblast growth factor (FGF), and transforming growth factor–β (TGF-β ) during acute allograft rejection. A 14-day postoperative course of immunosuppressive therapy with FK506 or rapamycin was administered. In situ hybridization was performed on serial full-thickness skin punch biopsies of the untreated rejecting limb allograft and compared with tissue from treated allografts, isografts, and to normal limb tissue. A sequential pattern of cytokine mRNA expression was demonstrated which progressed in a timedependent manner and paralleled observed clinical rejection. Maximal cytokine mRNA expression correlated with peak graft rejection. Cellular expression of IL-1α, IL-2, IL-6, γ-INF, FGF, and TGF-β mRNA was suppressed with FK506 to below isograft levels, and clinical rejection was not observed with the doses, routes, and schedules used. Rapamycin was ineffective in suppressing cytokine expression, and allograft rejection was not prevented. Isografts demonstrated no evidence of rejection. The in situ hybridization technique demonstrates a time-dependent, selective expression of cytokines within rejecting allograft tissue, and the modification of this response with immunosuppressive therapy. Down-regulation of cytokine expression is associated with clinical allograft survival.

We report a case of primary carcinoid of the kidney. The neoplasm had a trabecular growth pattern and was argyrophil positive and argentaffin negative. An extensive battery of immunohistochemical stains was negative for specific peptide products and keratin. Electron microscopy disclosed numerous cytoplasmic membrane-bound electron-dense core secretory granules and masses of intermediate microfilaments. A review of the pertinent medical literature revealed 5 previously reported cases.

Gastric cancer can be divided into two histologic types: intestinal and diffuse. To determine whether Helicobacter pylori, a bacterium linked with gastritis, was associated with either cancer type, we reviewed histologic sections from stomachs of patients who had undergone gastrectomy for gastric cancer. Of 37 of the sections with evidence of intestinal-type cancer, 33 (89.2%) contained H pylori in noncancerous tissue compared with 7 (31.8%) of 22 of the sections with evidence of diffuse-type cancer (odds ratio = 17.7; P.001). This association remained strong when controlled for age, sex, site, and number of sections reviewed. The prevalence of H pylori in intestinal-type gastric cancer far exceeded the prevalence of H pylori in diffuse disease and that described in the normal US population. This finding suggests that H pylori may be a cofactor in development of intestinal-type gastric cancer. [J Nati Cancer Inst 83:640–643, 1991]