Treatment of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis With Diffuse Alveolar Hemorrhage With Avacopan.

OBJECTIVE: Avacopan, an activated complement factor 5 receptor antagonist, has been approved as adjunct therapy for severe active antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Current evidence supports the management of AAV presenting with diffuse alveolar hemorrhage (DAH) by administering glucocorticoids combined with either rituximab or cyclophosphamide in addition to supportive care. The role of avacopan in patients with DAH as a primary severe disease manifestation of AAV has not been well established. Furthermore, concerns remain regarding timely access to avacopan, the best glucocorticoid tapering regimen, and long-term efficacy and safety of the drug. We sought to identify clinical features and outcomes of patients presenting with DAH secondary to AAV who received avacopan in addition to glucocorticoids and rituximab or cyclophosphamide. METHODS: We performed a retrospective cohort study of all consecutive patients presenting with DAH as part of active severe granulomatosis with polyangiitis or microscopic polyangiitis. Demographic and clinical characteristics were collected at presentation and follow-up. RESULTS: Fifteen patients met inclusion criteria and were observed for a median time of 17 weeks (interquartile range [IQR] 6-37 weeks) after initiation of avacopan. Patients were predominantly female and White, had never smoked, and were a median age of 66 years (IQR 52-72 years) at diagnosis. The majority had newly diagnosed severe AAV with renal involvement. Three patients progressed to respiratory failure. The timing of avacopan introduction and patterns of glucocorticoid tapers varied widely in this cohort. Two serious adverse events related to infection were observed, including one opportunistic infection leading to the patient's death, although neither was directly attributed to avacopan administration. CONCLUSION: We describe the clinical course of patients who presented with the severe AAV disease manifestation of DAH and received avacopan as adjunct therapy. Most patients achieved remission during follow-up, and adverse events, including infection, were observed.

Coccidioidomycosis in patients with various inflammatory disorders treated with tumor necrosis factor α inhibitors.

Coccidioides fungi are found primarily in the southwestern United States and are the cause of coccidioidomycosis. Tumor necrosis factor α inhibitors (TNFIs) are therapies for autoimmune and inflammatory conditions; their association with coccidioidomycosis is not well characterized. We aimed to determine the prevalence and characteristics of coccidioidomycosis among TNFI recipients with different inflammatory disorders at a tertiary care center. We retrospectively reviewed the electronic health records of patients at our institution from April 4, 2010 to December 17, 2017, who received TNFIs (infliximab, etanercept, adalimumab, certolizumab pegol, or golimumab) and had positive culture, pathologic, and/or serologic results for coccidioidomycosis. Among 1770 patients identified who received TNFIs, 49 (2.8%) had proven or probable coccidioidomycosis. Of these 49, 28 (57%) were men, 47 (96%) were White, and 42 (86%) had pulmonary coccidioidomycosis. The most common TNFIs used were adalimumab, infliximab, and etanercept. Coccidioidomycosis was identified in 25 of 794 patients with rheumatologic disorders (3.1%), 18 of 783 patients with inflammatory bowel disease (IBD) (2.3%), and six of 193 patients with dermatologic disorders (3.1%) (P = .34). There was no difference in coccidioidal infections among recipients of any particular TNFI agents. A minority of patients (7/49, 14%) had an extrapulmonary infection, and the majority of these (6/7) had IBD. Our study shows a low prevalence of coccidioidomycosis in TNFI recipients, even within the Coccidioides-endemic area. Persons with IBD were disproportionately represented among those with extrapulmonary coccidioidomycosis. Treatment with azoles was effective. LAY SUMMARY: Among 1770 patients who received tumor necrosis factor α inhibitors, 49 (2.8%) had newly acquired coccidioidomycosis over a 7-year period. Dissemination occurred in 14.3%, but disproportionately among those with underlying inflammatory bowel disease. All patients recovered with medical management.

Long-Term Safety of Rituximab in Granulomatosis With Polyangiitis and in Microscopic Polyangiitis.

OBJECTIVE: The present study was undertaken to conduct a phase IV, open-label, prospective study to characterize the long-term safety of rituximab in a 4-year observational registry of adult patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) within the US. METHODS: Patients initiating treatment with rituximab were evaluated every 6 months for up to 4 years. Outcomes included the incidence of serious adverse events (SAEs), infusion-related reactions (IRRs), and SAEs of specific interest, including serious infections, serious cardiac events, serious vascular events, and malignancies. RESULTS: Overall, 97 patients (72 with GPA and 25 with MPA) received rituximab through a median of 8 (range 1-28) infusions and were followed up for a median of 3.94 years (range 0.05-4.32 years). The estimated incidence rates (95% confidence interval [95% CI]) of serious infections, serious cardiac events, and serious vascular events were 7.11 (4.55-10.58), 5.03 (2.93-8.06), and 2.37 (1.02-4.67) per 100 patient-years (PYs), respectively. No IRRs or SAEs occurred within 24 hours of an infusion of rituximab. None of the 9 deaths reported (crude mortality rate 2.67 [95% CI 1.22-5.06] per 100 PYs) were considered to be related to use of rituximab. CONCLUSION: The safety profile of long-term treatment with rituximab in patients with GPA or MPA was consistent with that of rituximab administered for shorter durations and with rituximab's known safety profile in other autoimmune diseases for which it has received regulatory approval. These findings provide clinicians with long-term, practice-level safety data for rituximab in the treatment of GPA or MPA.

The Obesity Paradox in the Trauma Patient: Normal May not Be Better.

OBJECTIVE: The obesity paradox is the association of increased survival for overweight and obese patients compared to normal and underweight patients, despite an increased risk of morbidity. The obesity paradox has been demonstrated in many disease states but has yet to be studied in trauma. The objective of this study is to elucidate the presence of the obesity paradox in trauma patients by evaluating the association between BMI and outcomes. METHODS: Using the 2014-2015 National Trauma Database (NTDB), adults were categorized by WHO BMI category. Logistic regression was used to assess the odds of mortality associated with each category, adjusting for statistically significant covariables. Length of stay (LOS), ICU LOS and ventilator days were also analyzed, adjusting for statistically significant covariables. RESULTS: A total of 415,807 patients were identified. Underweight patients had increased odds of mortality (OR 1.378, p < 0.001 95% CI 1.252-1.514), while being overweight had a protective effect (OR 0.916, p = 0.002 95% CI 0.867-0.968). Class I obesity was not associated with increased mortality compared to normal weight (OR 1.013, p = 0.707 95% CI 0.946-1.085). Class II and Class III obesity were associated with increased mortality risk (Class II OR 1.178, p = 0.001 95% CI 1.069-1.299; Class III OR 1.515, p < 0.001 95% CI 1.368-1.677). Hospital and ICU LOS increased with each successive increase in BMI category above normal weight. Obesity was associated with increased ventilator days; Class I obese patients had a 22% increase in ventilator days (IRR 1.217 95% CI 1.171-1.263), and Class III obese patients had a 54% increase (IRR 1.536 95% CI 1.450-1.627). CONCLUSION: The obesity paradox exists in trauma patients. Further investigation is needed to elucidate what specific phenotypic aspects confer this benefit and how these can enhance patient care. LEVEL OF EVIDENCE: Level III, prognostic study.

Postacute Care Utilization in Postsurgical Orthogeriatric Hip Fracture Care.

INTRODUCTION: Among surgical patients, utilization of institutional-based postacute care (PAC) presents a notable financial burden and is associated with increased risk of complications and mortality rates when compared with discharge home. The purpose of this study was to identify predictors of postdischarge disposition to PAC in geriatric patients after surgical fixation of native hip fractures. METHODS: We have done a query of the American College of Surgeons National Surgical Quality Improvement Program to identify geriatric (≥65 years) patients who sustained surgical femoral neck, intertrochanteric, and subtrochanteric hip fractures in 2016. Multivariate regression was used to compute risk factors for discharge to and prolonged stay (>30 days) in PAC. RESULTS: Eight thousand one hundred thirty-three geriatric hip fracture patients with sufficient follow-up data were identified. Of these, 6,670 patients (82.0%) were initially discharged to PAC after their hip fracture episode of care, and 2,986 patients (36.7%) remained in PAC for >30 days. Age (odds ratio [OR] 1.06 [1.05 to 1.08], P < 0.001), partial (OR 2.41 [1.57 to 3.71], P < 0.001) or total dependence (OR 3.03 [1.92 to 4.46], P < 0.001) for activities of daily living, dementia (OR 1.62 [1.33 to 1.96], P < 0.001), diabetes (OR 1.46 [1.14 to 1.85], P = 0.002), hypertension (OR 1.32 [1.10 to 1.58], P = 0.002), and total hospital length of stay (OR 1.04 [1.01 to 1.08], P = 0.006) were independent risk factors for discharge to PAC. Age (OR 1.05 [1.04 to 1.06], P < 0.001), partial (OR 2.86 [1.93 to 3.79], P < 0.001) or total dependence (OR 3.12 [1.45 to 4.79], P < 0.001) for activities of daily living, American Society of Anesthesiologist's classification (OR 1.27 [1.13 to 1.43], P < 0.001), dementia (OR 1.49 [1.28 to 1.74], P < 0.001), and total hospital length of stay (OR 1.10 [1.08 to 1.13], P < 0.001) were independent risk factors for prolonged PAC stay >30 days. DISCUSSION: Discharge to PAC is the norm among patients undergoing hip fracture surgery. Provider foreknowledge of risk factors may help improve hip fracture outcomes and decrease healthcare costs.

Marijuana use and outcomes in adult and pediatric trauma patients after legalization in California.

BACKGROUND: Marijuana has become legal in eight states since 2012. We hypothesized the incidence of marijuana-positive trauma patients and rate of mortality has increased post-legalization. METHODS: A single level-I trauma center was used to identify patients screening positive for marijuana on urine-toxicology. Patients in the pre-legalization and post-legalization periods were compared. RESULTS: In the pre-legalization cohort 9.4% were marijuana-positive versus 11.0% in the post-legalization cohort (p = 0.001). Marijuana-positive patients post-legalization had higher rates of critical trauma activation (20.0% vs. 15.0%, p = 0.01) and mortality (2.6% vs. 1.2%, p = 0.03). In the pediatric (age 12-17) subgroup, the incidence of marijuana-positive patients did not change after legalization (pre: 39.3%, post: 46.4%, p = 0.24). CONCLUSION: The incidence of marijuana-positive trauma patients increased post-legalization. Adult marijuana-positive trauma patients post-legalization were more likely to meet criteria for critical trauma activation and have a higher mortality rate. A subgroup of pediatric patients had an alarmingly high rate of marijuana use. SUMMARY: The rate of marijuana use among trauma patients increased post-legalization in California. The rate of critical trauma activation also increased as well as the mortality rate.

The Utility of Screening for Coccidioidomycosis in Recipients of Inhibitors of Tumor Necrosis Factor α.

BACKGROUND: Tumor necrosis factor α inhibitors (TNFi) are commonly used to treat immune-mediated disorders, but they are associated with an increased risk of mycobacterial and fungal infections. We compared the outcomes of TNFi recipients screened for asymptomatic coccidioidomycosis with those of unscreened patients to compare the development of symptomatic coccidioidomycosis and to describe its outcomes for patients with abnormal coccidioidal screenings. METHODS: We searched electronic health records from 4 September 2010 through 26 September 2016 for all patients receiving a TNFi for dermatologic, rheumatologic, or gastroenterologic diagnoses, then categorized patients by whether or not they had undergone coccidioidal serologic testing for screening or diagnostic purposes. RESULTS: A total of 2793 patients had a TNFi prescribed. Of those, 1951 met the inclusion criteria: 1025/1951 (52.5%) never had coccidioidal screening; 925/1951 (47.4%) had serologic screening either before beginning TNFi therapy or annually, or both after beginning a TNFi. Symptomatic coccidioidomycosis developed in 35/1025 (3.4%) unscreened patients. Of those screened, 861/925 (93.1%) had negative serologic tests, of which 11/861 (1.3%) subsequently developed symptomatic coccidioidomycosis; 36/925 (3.9%) had coccidioidomycosis at screening (7, probable infection; 11, possible infection; 18, asymptomatic seropositive result); and 17 had only positive findings for immunoglobulin M antibodies and did not meet the definition for coccidioidomycosis. The unscreened cohort was more likely to have symptomatic coccidioidomycosis than the screened cohort (35/1025 vs 11/861, P < .01). CONCLUSIONS: Screening for asymptomatic coccidioidomycosis within a Coccidioides-endemic area allowed for identifying and managing asymptomatic coccidioidomycosis before patients began TNFi therapy. Less symptomatic infection developed in the screened than the unscreened cohort.

Breast carcinoma in young women.

OBJECTIVE: To estimate the incidence of breast carcinoma and survival in patients younger than 25 years old, and to describe presenting clinical signs and symptoms of breast cancer in this age group. METHODS: A population-based descriptive study and case review in Olmsted County, Minnesota, was conducted using the resources of the Rochester Epidemiology Project. Participants were Olmsted County girls and women younger than 25 years old with histopathologically confirmed breast carcinoma diagnosed between 1935 and 2005. Nonresidents who presented to a medical facility within Olmsted County during this time period were included in some portions of the analysis. Main outcome measures were age-adjusted incidence, 5-year survival, and clinical presentation of breast carcinoma in girls and women younger than 25 years of age. RESULTS: With four breast carcinomas observed in Olmsted County residents over 1,201,539 person-years, the annual age-adjusted incidence of breast cancer in this population was 3.2 per million (95% confidence interval, 0.1-6.2). All four cancers occurred in the 20- to 24-year age group (age-specific incidence, 16.2 per million). Eight additional cases of breast carcinoma were identified in nonresidents. Delay in diagnosis was common. All had at least one feature worrisome for an aggressive neoplasm identified in their clinical history, on physical examination or by imaging. CONCLUSION: Breast carcinoma in young women is very rare, associated with delayed diagnosis, and usually associated with concerning features requiring biopsy. LEVEL OF EVIDENCE: III.

Coccidioidomycosis in rheumatology patients: incidence and potential risk factors.

Coccidioidomycosis is a potentially serious fungal infection contracted in endemic areas of the desert southwestern United States. Limited information exists about its incidence and clinical course in patients with rheumatic diseases, who may be at higher risk of symptomatic or disseminated coccidioidomycosis because of either the rheumatic disease itself or its treatment. We analyzed the incidence and risk factors for symptomatic and complicated coccidioidomycosis in our academic rheumatology practice in central Arizona. Between January 1, 2000, and June 30, 2006, coccidioidomycosis was diagnosed in 1.9% of the overall practice and in 3.1-3.6% of patients with rheumatoid arthritis (RA). The annual incidence was 1% in patients recently diagnosed with RA and 2% among patients with recently initiated infliximab treatment. Coccidioidomycosis was identified only in patients with inflammatory rheumatic diseases and extrathoracic dissemination occurred only to joints in two patients. Corticosteroids, immunosuppressive medications, and tumor necrosis factor inhibitors (TNFIs) appeared to be risk factors for symptomatic, but not disseminated coccidioidomycosis.

Changes in the functional structure of the tenosynovium in idiopathic carpal tunnel syndrome: a scanning electron microscope study.

BACKGROUND: The subsynovial connective tissue lies between the flexor tendons and visceral synovium in the carpal tunnel. Although tenosynovial fibrosis is nearly universally noted in patients with carpal tunnel syndrome, the relationship, if any, between the fibrosis and nerve abnormalities is unknown. The authors used light and scanning electron microscope imaging of the subsynovial connective tissue to gather information about its organization. METHODS: Human subsynovial connective tissue was studied to determine its ultrastructural morphology. Biopsy specimens of 11 patients (12 hands) with idiopathic carpal tunnel syndrome, 14 cadaver controls, and two cadavers with a history of carpal tunnel syndrome were obtained for scanning electron microscopic imaging and histopathologic examination. RESULTS: The visceral synovial layer is an uninterrupted membrane that defines the bursa dorsally. The subsynovial connective tissue consists of fibrous bundles that run parallel to the tendon, interconnected by smaller fibrous fibers. It connects to the synovial membrane and the flexor tendons. During tendon motion, the loose fibers between adjacent layers are stretched. The control tissue showed interconnections between all the parallel layers, whereas in patients with idiopathic carpal tunnel syndrome, these interconnections were absent, replaced with thicker parallel fibrous bundles. Similar changes were found in the cadaver carpal tunnel syndrome specimens. Pathologic changes in the patient and cadaver carpal tunnel syndrome specimens were most apparent close to the tendon and became progressively less severe in more superficial layers. CONCLUSIONS: The authors' observation that the most severe changes in the subsynovial connective tissue were found close to the tendon suggests that these changes may be the result of a shearing injury.

Morphological changes of collagen fibrils in the subsynovial connective tissue in carpal tunnel syndrome.

BACKGROUND: Pathologic changes occur commonly in the subsynovial connective tissue in patients with carpal tunnel syndrome. The purposes of this study were to investigate the ultrastructural changes of the subsynovial connective tissue in these patients and compare them with the findings in cadaver controls. METHODS: The diameter and density of collagen fibrils were measured by transmission electron microscopy in specimens of subsynovial connective tissue from ten patients with idiopathic carpal tunnel syndrome and from ten fresh-frozen cadavers of individuals without known symptoms of carpal tunnel syndrome. RESULTS: We noted deformed collagen fibrils with a spiraled appearance in the specimens from the patients. We also observed phagocytosis of elastin fibrils in all of those specimens. These changes were noted only rarely in the cadaver controls. The mean diameter (and standard deviation) of the collagen fibrils was 45.5 +/- 8.0 nm in the control group and 54.8 +/- 15.2 nm in the patient group (p < 0.05). The mean number of collagen fibrils per 0.04 microm2 (density) was 201.38 +/- 48.88 in the control group and 157.08 +/- 54.38 in the patient group (p < 0.05). CONCLUSIONS: These ultrastructural findings suggest that subsynovial collagen in patients with carpal tunnel syndrome is structurally different from that in individuals without carpal tunnel syndrome, but the processes resulting in that abnormal morphology remain to be elucidated.

Randomized trial of tamoxifen alone or combined with fluoxymesterone as adjuvant therapy in postmenopausal women with resected estrogen receptor positive breast cancer. North Central Cancer Treatment Group Trial 89-30-52.

PURPOSE: This clinical trial evaluated the addition of fluoxymesterone (Flu) to tamoxifen (Tam) in women with resected early stage breast cancer and attempted to corroborate the findings of superiority for the combination over Tam alone seen in a previous randomized trial in metastatic disease. PATIENTS AND METHODS: Postmenopausal women with early stage breast cancer that was known to be estrogen receptor (ER) positive were randomized to treatment with Tam (20 mg per day orally for 5 years) alone or combined with Flu (10 mg orally twice per day for 1 year). The primary endpoint was relapse-free survival (RFS) defined as local-regional or distant recurrence including ductal carcinoma in situ of the ipsilateral, but not contralateral breast, and death from any cause. RESULTS: There were 541 eligible patients entered between 1991 and 1995 and the treatment arms were balanced with respect to patient characteristics. The median follow up of patients still alive was 11.4 years. No significant difference was found between Tam plus Flu and Tam alone in terms of RFS or overall survival. The adjusted hazard ratio (Tam+Flu/Tam) for relapse or death without relapse was estimated to be 0.84 (95% CI: 0.64-1.10) and that for death was 0.89 (95% CI: 0.67-1.18). As expected there was more virilization in women who received Flu. CONCLUSIONS: This clinical trial did not demonstrate superiority of Tam plus Flu over Tam alone as adjuvant therapy for postmenopausal women with resected early breast cancer known to be ER positive.

Dedifferentiated chondrosarcoma: the role of chemotherapy with updated outcomes.

BACKGROUND: There are very few published data on the survival of patients with dedifferentiated chondrosarcoma, or, more specifically, on the efficacy and role of chemotherapy, especially in the era of modern diagnostic and treatment modalities. The current study examines the influence of advancements in imaging and chemotherapy on outcome and serves as an extension to a previous study published in 1986. METHODS: Forty-two patients with dedifferentiated chondrosarcoma who had presented to our institution between 1986 and 2000 were identified, and a retrospective chart review was performed. The study group included twenty-four men and eighteen women with an average age of sixty-six years. The diagnosis of dedifferentiated chondrosarcoma was verified histologically, and data on treatment, adjuvant therapy, and survival were obtained from the medical records of all patients. All patients had been followed for a minimum of twenty-four months. RESULTS: The tumors were classified, according to the system of the Musculoskeletal Tumor Society, as grade IIA (five), grade IIB (twenty-six), and grade III (eleven). Three patients underwent biopsy only, eighteen had a limb-sacrificing procedure, and twenty-one had a limb-sparing procedure. In the group of patients who underwent resection, the surgical margins were classified as intralesional in three, marginal in two, wide in nineteen, and radical in fifteen. Twenty-seven patients received neoadjuvant therapy; of these, twenty-three received chemotherapy only, two received radiotherapy only, and two received combined therapy. The median survival time was 7.5 months, and the five-year rate of disease-free survival was 7.1%. With the numbers available, there was no significant difference in the rate of disease-free survival with respect to the use of chemotherapy (p = 0.54), the location of surgical margins (p = 0.14), the histological subtype (p = 0.87), the tumor stage at the time of diagnosis (p = 0.43), the tumor size (p = 0.79), or the performance of limb-sparing as opposed to limb-sacrificing procedures (p = 0.42). CONCLUSIONS: Despite advances in diagnostic modalities and adjuvant therapies, dedifferentiated chondrosarcoma continues to carry a poor prognosis. While local control is achieved in the majority of cases, distant disease remains the greatest clinical challenge, developing in 90% of patients. Efforts are needed to continue to encourage earlier diagnosis and to develop effective adjuvant therapies for the control of distant disease. The routine use of current adjuvant chemotherapy and its inherent risks in this population should be reconsidered.

Radiographic, CT, and MR imaging features of dedifferentiated chondrosarcomas: a retrospective review of 174 de novo cases.

Up to 11% of chondrosarcomas may undergo regional anaplastic change, resulting in a high-grade noncartilaginous sarcoma arising within a typically low-grade chondrosarcoma. Known as dedifferentiated chondrosarcomas, these tumors are highly malignant with a very poor prognosis. The most important factor affecting survival is an accurate preoperative diagnosis. Therefore, the ability to predict the possibility of dedifferentiation in a malignant cartilage tumor on the basis of imaging findings is critical to ensure adequate tumor sampling at the time of biopsy. Imaging findings at radiography, computed tomography (CT), and magnetic resonance (MR) imaging in 174 patients with dedifferentiated chondrosarcoma were reviewed to determine whether there are radiologic features that can help predict dedifferentiation. On approximately one-third of the radiographs, one-third of the MR images, and one-half of the CT scans, the tumors demonstrated bimorphic features (ie, distinctly different tumor features juxtaposed within the lesion), most frequently a dominant lytic area adjacent to a mineralized tumor at radiography and a large, unmineralized soft-tissue mass associated with an intraosseous chondroid-containing tumor at CT and MR imaging. In the initial evaluation of patients with a primary bone tumor, thorough evaluation of the radiologic features of the entire tumor is critical.

Imaging mass lesions by vibro-acoustography: modeling and experiments.

Vibro-acoustography is a recently developed imaging method based on the dynamic response of to low-frequency vibration produced by of ultrasound radiation force. The main differentiating feature of this method is that the image includes information about the dynamic properties of the object at the frequency of the vibration, which is normally much lower than the ultrasound frequency. Such information is not available from conventional ultrasound imaging. The purpose of this study is to evaluate the performance of vibro-acoustography in imaging mass lesions in soft tissue. Such lesions normally have elastic properties that are different from the surrounding tissue. Here, we first present a brief formulation of image formation in vibro-acoustography. Then we study vibro-acoustography of solid masses through computer simulation and in vitro experiments. Experiments are conducted on excised fixed liver tissues. Resulting images show lesions with enhanced boundary and often with distinctive textures relative to their background. The results suggest that vibro-acoustography maybe a clinically useful imaging modality for detection of mass lesions.

A histological and immunohistochemical study of the subsynovial connective tissue in idiopathic carpal tunnel syndrome.

BACKGROUND: The most common histological finding in carpal tunnel syndrome is noninflammatory synovial fibrosis. The accumulated effect of minor injuries is believed to be an important etiologic factor in some cases of carpal tunnel syndrome. We sought evidence of such injuries in the synovial tissue of patients with carpal tunnel syndrome and in cadaver controls. METHODS: We compared synovial specimens from thirty patients who had idiopathic carpal tunnel syndrome with specimens from a control group of ten fresh-frozen cadavers of individuals who had not had an antemortem diagnosis of carpal tunnel syndrome and who met the same exclusion criteria. Analysis included histological and immunohistochemical examination for the distribution of collagen types I, II, III, and VI and transforming growth factor-beta (TGF-beta) RI, RII, and RIII. RESULTS: Histological examination showed a marked increase in fibroblast density, collagen fiber size, and vascular proliferation in the specimens from the patients compared with the control specimens (p < 0.001). Collagen types I and II were not found in the synovium of either the patients or the controls, but collagen type VI was a major component of both. Collagen type-III fibers were more abundant in the patients than in the controls (p < 0.001). Expression of TGF-beta RI was found in the endothelial cells and fibroblasts in the patient and control specimens, with a marked increase in expression in the fibroblasts of the patients compared with that in the control tissue (p < 0.001). CONCLUSIONS: These findings are similar to those after injury to skin, tendon, and ligament and suggest that patients with idiopathic carpal tunnel syndrome may have sustained an injury to the subsynovial connective tissue.

Performance of vibro-acoustography in detecting microcalcifications in excised human breast tissue: a study of 74 tissue samples.

X-ray mammography is the principal modality used today for detection of breast microcalcifications and breast lesions associated with breast cancer. X-ray mammography, however, is ionizing and its sensitivity is greatly reduced in dense breasts. Hence, alternative noninvasive and nonionizing breast imaging tools that can aid physicians to better diagnose early-stage breast lesions are of great interest. Vibro-acoustography is a novel noninvasive imaging technique that uses ultrasound in a fundamentally new way. This method uses the radiation force of ultrasound to vibrate the tissue at low (kilohertz) frequency and records the resulting response to produce images that are related to the mechanical properties of the tissue. The goal of this study is to evaluate the performance of vibro-acoustography in detecting breast microcalcifications by conducting vibro-acoustography on 74 fixed breast tissue samples with known microcalcifications based on their radiographs. The results indicate that in most cases micro-calcifications can be detected by vibro-acoustography. Further development of vibro-acoustography may lead to a novel-imaging tool for in vivo detection of microcalcifications.

Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature.

Oncogenic osteomalacia (OO) is a rare paraneoplastic syndrome of osteomalacia due to phosphate wasting. The phosphaturic mesenchymal tumor (mixed connective tissue variant) (PMTMCT) is an extremely rare, distinctive tumor that is frequently associated with OO. Despite its association with OO, many PMTMCTs go unrecognized because they are erroneously diagnosed as other mesenchymal tumors. Expression of fibroblast growth factor-23 (FGF-23), a recently described protein putatively implicated in renal tubular phosphate loss, has been shown in a small number of mesenchymal tumors with known OO. The clinicopathological features of 32 mesenchymal tumors either with known OO (29) or with features suggestive of PMTMCT (3) were studied. Immunohistochemistry for cytokeratin, S-100, actin, desmin, CD34, and FGF-23 was performed. The patients (13 male, 19 female) ranged from 9 to 80 years in age (median 53 years). A long history of OO was common. The cases had been originally diagnosed as PMTMCT (15), hemangiopericytoma (HPC) (3), osteosarcoma (3), giant cell tumor (2), and other (9). The tumors occurred in a variety of soft tissue (21) and bone sites (11) and ranged from 1.7 to 14 cm. Twenty-four cases were classic PMTMCT with low cellularity, myxoid change, bland spindled cells, distinctive "grungy" calcified matrix, fat, HPC-like vessels, microcysts, hemorrhage, osteoclasts, and an incomplete rim of membranous ossification. Four of these benign-appearing PMTMCTs contained osteoid-like matrix. Three other PMTMCTs were hypercellular and cytologically atypical and were considered malignant. The 3 cases without known OO were histologically identical to the typical PMTMCT. Four cases did not resemble PMTMCT: 2 sinonasal HPC, 1 conventional HPC, and 1 sclerosing osteosarcoma. Three cases expressed actin; all other markers were negative. Expression of FGF-23 was seen in 17 of 21 cases by immunohistochemistry and in 2 of 2 cases by RT-PCR. Follow-up (25 cases, 6-348 months) indicated the following: 21 alive with no evidence of disease and with normal serum chemistry, 4 alive with disease (1 malignant PMTMCT with lung metastases). We conclude that most cases of mesenchymal tumor-associated OO, both in the present series and in the reported literature, are due to PMTMCT. Improved recognition of their histologic spectrum, including the presence of bone or osteoid-like matrix in otherwise typical cases and the existence of malignant forms, should allow distinction from other mesenchymal tumors. Recognition of PMTMCT is critical, as complete resection cures intractable OO. Immunohistochemistry and RT-PCR for FGF-23 confirm the role of this protein in PMTMCT-associated OO.