High school football and risk of neurodegeneration: a community-based study.

OBJECTIVE: To assess whether high school football played between 1946 and 1956, when headgear was less protective than today, was associated with development of neurodegenerative diseases later in life. METHODS: All male students who played football from 1946 to 1956 in the high schools of Rochester, Minnesota, plus a non-football-playing referent group of male students in the band, glee club, or choir were identified. Using the records-linkage system of the Rochester Epidemiology Project, we reviewed (from October 31, 2010, to March 30, 2011) all available medical records to assess later development of dementia, Parkinson disease (PD), or amyotrophic lateral sclerosis (ALS). We also compared the frequency of dementia, PD, or ALS with incidence data from the general population of Olmsted County, Minnesota. RESULTS: We found no increased risk of dementia, PD, or ALS among the 438 football players compared with the 140 non-football-playing male classmates. Parkinson disease and ALS were slightly less frequent in the football group, whereas dementia was slightly more frequent, but not significantly so. When we compared these results with the expected incidence rates in the general population, only PD was significantly increased; however, this was true for both groups, with a larger risk ratio in the non-football group. CONCLUSION: Our findings suggest that high school students who played American football from 1946 to 1956 did not have an increased risk of later developing dementia, PD, or ALS compared with non-football-playing high school males, despite poorer equipment and less regard for concussions compared with today and no rules prohibiting head-first tackling (spearing).

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.

Dextrose-induced subsynovial connective tissue fibrosis in the rabbit carpal tunnel: A potential model to study carpal tunnel syndrome?

In this pilot study, hypertonic dextrose solution was used to induce fibrosis of the subsynovial connective tissue (SSCT) and create an animal model of potential use in the study of carpal tunnel syndrome (CTS). The SSCT of the carpal tunnel in 15 New Zealand white rabbits were injected with 0.05 ml of 10% dextrose solution in 1 paw and 0.05 ml of saline in the contralateral paw, to serve as a control. The animals were killed at 1, 2, 4, 8, or 12 weeks. While the saline side showed minimal changes at any time period, the hypertonic dextrose side showed progressive noninflammatory SSCT fibrosis, with vascular proliferation and thickening of collagen bundles. Demyelination of the median nerve developed at 12 weeks after the injection on the dextrose side. These findings are similar to the progression of pathology noted in humans with CTS.

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.

Immunolocalization of collagen types in the subsynovial connective tissue within the carpal tunnel in humans.

The tenosynovium within the carpal tunnel consists of a single layer of synovial cells, which lines the bursae within the carpal tunnel, and the subsynovial connective tissue (SSCT), which contains the tendon vasculature and other structural elements. In this study, we used immunogold labeling to localize collagen types within the SSCT in three cadaver specimens and three patients with carpal tunnel syndrome. Positive labeling for collagen types I, III and VI was found with immunoelectron microscopy. Collagen types I and III were codistributed within the SSCT. Type VI was primarily located in microfibrillar structures between collagen bundles, between elastin and collagen bundles and between collagen bundles and cells. There was no difference in the distribution of collagen types when comparing cadaver specimens and carpal tunnel patients.

Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate.

PURPOSE: To determine whether the addition of ifosfamide and/or muramyl tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could improve the probability for event-free survival (EFS) in newly diagnosed patients with osteosarcoma (OS). PATIENTS AND METHODS: Six hundred seventy-seven patients with OS without clinically detectable metastatic disease were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive surgical resection of the primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 double dagger 2 factorial design. The primary end point for analysis was EFS. RESULTS: Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP. The addition of MTP to standard chemotherapy achieved a 3-year EFS rate of 68%. The addition of ifosfamide to standard chemotherapy achieved a 3-year EFS rate of 61%. The addition of both ifosfamide and MTP resulted in a 3-year EFS rate of 78%. CONCLUSION: The addition of ifosfamide in this dose schedule to standard chemotherapy did not enhance EFS. The addition of MTP to chemotherapy might improve EFS, but additional clinical and laboratory investigation will be necessary to explain the interaction between ifosfamide and MTP.

Correlation of histopathologic findings with clinical outcome in necrotizing fasciitis.

BACKGROUND: Necrotizing fasciitis is an uncommon disease with high morbidity and mortality rates. Little is known about the role of histopathologic examination in disease prognosis. METHODS: A retrospective study was conducted to determine what correlations, if any, exist between the histopathologic features of resected tissue in patients with necrotizing fasciitis and clinical outcome. RESULTS: Eighty-two cases of necrotizing fasciitis that occurred between January 1990 and December 2002 were identified. Histopathologic findings were available for review in 63 cases. A novel histopathologic classification scheme, based on hematoxylin-eosin and Gram stain results, was developed. The classification scheme included 3 stages: stage I, characterized by an intense neutrophilic response and an absence of bacteria in infected tissue; stage II, characterized by the presence of a moderate-to-severe neutrophilic response and positive Gram stain results or by minimal to absent neutrophilic response with a negative Gram stain result; and stage III, characterized by the presence of few or no polymorphonuclear leukocytes and a Gram stain result positive for bacteria during histopathologic examination. Patients with stage I findings had a significantly lower risk of death than patients with stage III findings (7.1% vs. 47%; odds ratio [OR], 0.1; 95% confidence interval [CI], 0.01-0.8; P=.03). Patients with stage II findings had a significantly lower mortality rate than patients with stage III findings (14.2% vs. 47%; OR, 0.2; 95% CI, 0.04-0.9; P=.04). Due to the small number of deaths (n=11) in patients for whom histopathologic examination of resected tissue was performed, multivariate analysis was not done. CONCLUSIONS: Results of this study suggest that histopathologic findings may correlate with clinical outcome in cases of necrotizing fasciitis. Because the histopathologic scheme is based on results of commonly available stains, it could be easily adopted for use in other institutions that could further evaluate its usefulness as a prognostic tool.

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.

Vascular pathologic changes in the flexor tenosynovium (subsynovial connective tissue) in idiopathic carpal tunnel syndrome.

We used the Verhoeff-van Gieson stain method to identify histopathology and to localize elastin in the subsynovial connective tissue of the tendon sheath (SSCT) of the middle finger flexor digitorum superficialis (FDS) within the carpal tunnel in 10 carpal tunnel syndrome (CTS) patients and 10 control cadaver specimens. Normal SSCT stained for elastin abundantly around blood vessels and within vessel walls. The typical pathologic findings of CTS patients SSCT included vascular proliferation, vascular hypertrophy, and vascular obstruction with wall thickening. There was a decreased amount of elastin in the blood vessel walls and around the vessels in the CTS patients as well. The changes in the carpal tunnel patients were particularly remarkable in that the patients were younger than the controls, yet showed findings more characteristic of chronic degeneration.

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.

Biocompatibility of a physiological pressure sensor.

A newly developed fiber optic micropressure sensor was evaluated for biocompatibility using the International Organization for Standardization (ISO) test standard 10993-6. The test material and an inert control (fused silica glass) were tested in New Zealand white rabbits. Four test specimens were implanted in the paravertebral muscles on one side of the spine about 2-5 cm from the mid-line and parallel to the spinal column. Similarly, four control specimens were implanted on the opposite side. The implantation periods were 1, 4, and 12 weeks to ensure a steady state biological tissue response. Four animals were tested at each time period. Macroscopic and microscopic observations were performed to compare the biological reactions between the test and control materials. There was an inflammatory reaction at 1 week which subsided at 4 weeks. There was fibrous tissue growth near the implant that also decreased over time. Most importantly, there was no significant difference in the biological response between the test and control materials. Therefore, we conclude that the pressure microsensor is biocompatible.