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Although there are adequate therapies for Graves' hyperthyroidism, mild to moderate Graves' orbitopathy (GO) is usually treated symptomatically whereas definitive therapy is reserved for severe, vision-threatening GO. Importantly, none of the treatment regimens for Graves' disease used today are directed at the pathogenesis of the disease. Herein, we review some aspects of what is known about the pathogenesis of these 2 major components of Graves' disease, specifically the apparent important roles of the TSH and IGF-1 receptors, and thereafter describe future therapeutic approaches directed at these receptors. We propose that targeting these receptors will yield effective and better tolerated treatments for Graves' disease, especially for GO.

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Synthetic cannabinoid use has become widespread, leading to increased burdens on health care providers. Symptoms range from agitation and psychosis to seizures and acute kidney injury. We report a case where a patient was assessed and treated twice within 12 h for seizures following synthetic cannabinoid intoxication. Blood sample determinations showed low concentrations of analogues not previously reported, some of which are legal. Clinicians should be aware that synthetic cannabinoids may cause an array of severe health consequences. Given the ever evolving structure of available analogues, clinicians must also be prepared for other unexpected adverse effects.

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Histone deacetylases (HDACs) are frequently overexpressed in broad range of cancer types, where they alter cellular epigenetic programming to promote cell proliferation and survival. However, the mechanism by which HDACs become overexpressed in human cancers remains somewhat of a mystery. In this study, we investigated the expression and functional significance of miR-449a in prostate cancer cells. Using real-time PCR, we found that miR-449a is downregulated in prostate cancer tissues relative to patient-matched control tissue. Introduction of miR-449a into PC-3 prostate cancer cells resulted in cell-cycle arrest, apoptosis and a senescent-like phenotype. In silico analysis of 3'-UTR regions identified a number of genes involved in cell-cycle regulation as putative targets of miR-449a. Using a luciferase 3'-UTR reporter system, we established that HDAC-1 (histone deacetylase 1), a gene that is frequently overexpressed in many types of cancer, is a direct target of miR-449a. Further, our data indicate that miR-449a regulates cell growth and viability in part by repressing the expression of HDAC-1 in prostate cancer cells. Our findings provide new insight into the function of miRNA in regulating HDAC expression in normal versus cancerous tissue.

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Astrocyte-elevated gene-1 (AEG-1) has been reported to be upregulated in several malignancies and play a critical role in Ha-ras-mediated oncogenesis through the phosphatidylinositol 3-kinase/AKT signaling pathway. However, the role of AEG-1 in prostate cancer (PC) has never been reported. We now show that AEG-1 is overexpressed in clinical PC tissue samples and cultured PC cells compared to benign prostatic hyperplasia tissue samples and normal prostate epithelial cells. Interestingly, AEG-1 knockdown induced cell apoptosis through upregulation of forkhead box (FOXO) 3a activity. This alteration of FOXO3a activity was dependent on reduction of AKT activity in LNCaP and PC-3 cells with high constitutive AKT activity, but not in DU145 cells with low constitutive AKT activity, although AEG-1 knockdown had no impact on phosphatase and tensin homolog expression in these cells. AEG-1 knockdown also attenuated the constitutive activity of the nuclear factor kappaB (NF-kappaB) and the activator protein 1 (AP-1) with a corresponding depletion in the expression of NF-kappaB and AP-1-regulated genes (interleukin (IL)-6, IL-8 and matrix metalloproteinase-9) and significantly decreased cell invasion properties of PC-3 and DU145 cells. Overall, our findings suggest that aberrant AEG-1 expression plays a dominant role as a positive auto-feedback activator of AKT and as a suppressor of FOXO3a in PC cells. AEG-1 may therefore represent a novel genetic biomarker to serve as an attractive molecular target for new anticancer agents to prevent PC cell progression and metastasis.

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PURPOSE: Giant condyloma acuminatum (Buschke-Loewenstein tumor) of the anorectum is a rare disease with a potentially fatal course. Controversy exists as to the epidemiology, pathologic nature, and management of the tumor. METHODS: We present a 42-year-old male with a 12-cm x 10-cm exophytic mass of the anal verge. Treatment included wide local excision and partial closure with rotation flaps. Pathology revealed a giant condyloma acuminatum with foci of well-differentiated squamous-cell carcinoma. We identified 51 reported cases of giant condyloma acuminatum in the English literature, and to our knowledge this is the largest review to date. RESULTS: Giant condyloma acuminatum presents with a 2.7:1 male-to-female ratio. For patients younger than 50 years of age, this ratio is increased to 3.5:1. The mean age at presentation is 43.9 years, 42.9 in males and 46.6 in females (P = 0.44). There seems to be a recent trend toward a younger presentation. The most common presenting symptoms are perianal mass (47 percent), pain (32 percent), abscess or fistula (32 percent), and bleeding (18 percent). Giant condyloma acuminatum has been linked to human papilloma virus and has distinct histologic features. Foci of invasive carcinoma are noted in 50 percent of the reports, "carcinoma in situ" in 8 percent, and no invasion in 42 percent. Historically, treatment strategies have included topical chemotherapy, wide local excision, abdominopelvic resection, and the frequent addition of adjuvant and neoadjuvant systemic chemotherapy and radiation therapy. Recurrence is common. CONCLUSION: There seems to be a trend toward younger age at presentation and male predominance of giant condyloma acuminatum of the anorectum. Foci of invasive cancer within giant condyloma specimens are of uncertain significance and do not seem to correlate with recurrence or prognosis. Local invasion and local recurrence are the major source of morbidity in this disease. Complete excision is the preferred initial therapy when feasible. Wide local excision, fecal diversion, or abdominoperineal resection have been used. Chemotherapy with 5-fluorouracil and focused radiation therapy may be used in certain cases of recurrence or extensive pelvic disease, with unpredictable response. Controlled, prospective, multi-institutional studies are necessary to further define the nature and treatment of this rare disease.

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Blue rubber bleb nevus syndrome is an uncommon condition manifested by gastrointestinal and skin hemangiomas that lead to gastrointestinal bleeding and anemia. The purpose of this report is to present a case with long-term follow-up. The patient is a 37-year-old female with a life-long history of blue rubber bleb nevus syndrome. She underwent multiple resectional operations that combined to give her a partial gastrectomy, partial small bowel resection, total abdominal colectomy, and end ileostomy. She continues to need endoscopy with sclerotherapy. In addition, she has iron-deficiency anemia, nephrolithiasis, major depression, and malnutrition despite vitamin and caloric supplements. There are no other reports showing these complications of blue rubber bleb nevus syndrome or with this length of follow-up. Therapy for blue rubber bleb nevus syndrome should be conservative if possible, because operative therapy may lead to significant long-term complications.

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PURPOSE: With improved antiretroviral therapy, HIV-positive patients are achieving a longer life expectancy. An increased incidence of anal squamous cell carcinomas has been noted in these patients. The purpose of this study was to determine the outcome of HIV-positive patients with anal squamous cell carcinomas. METHODS: We conducted a review based on our tumor registry from 1980 through 1999. We identified 73 patients with anal squamous cell carcinoma treated at the University of Texas Southwestern Medical Center affiliated hospitals; 23 were HIV positive (18 had AIDS). In the HIV-positive group, 9 had in situ squamous carcinomas and 14 had invasive squamous cell carcinomas. Data collected included age, CD4 count, treatment, complications, and survival; these data were analyzed by Student's t-test. RESULTS: All patients were male. Those with squamous cell cancer of the anus were offered radiation therapy and chemotherapy. Beginning in 1998, all patients received highly active antiretroviral therapy before treatment. Seven of 14 anal squamous cell carcinoma patients had their therapy adjusted owing to toxicity. Morbidity included proctocolitis and diarrhea (n = 2) requiring diversion (n = 1), hemorrhagic cystitis (n = 1), neutropenic fever (n = 3), bone marrow suppression (n = 1), and urethral stricture (n = 1). Mean age was 42 years for anal squamous cell carcinoma patients and 36 years for squamous cell carcinoma in situ patients (P = 0.05). Mean CD4 count was 222 cells/ml in patients with infiltrating carcinoma and 200 in the in situ patients (P = NS). One-year and five-year mortality rates, respectively, were 40 percent and 80 percent for infiltrating carcinoma patients and 17 percent and 50 percent for the in situ patients. Both of the in situ patients who died had CD4 counts <20 cells/ml at diagnosis, whereas the rest had CD4 counts >100 cells/ml and are currently without anal disease. Mean CD4 count at diagnosis for all patients who died was 133 cells/ml, whereas for those surviving, it was 261 cells/ml (P = 0.03). Eight (all with infiltrating carcinoma) of the 10 patients who died had persistent anal disease, but none had metastasis. CONCLUSION: HIV-positive patients with in situ carcinomas present at an earlier age than those with infiltrating lesions. In situ patients with CD4 counts as low as 105 cells/ml do well with local excision. A low CD4 count at diagnosis without highly active antiretroviral therapy predicts a poor prognosis. Because these patients appear to succumb to their HIV status and not the anal disease, anal squamous cell carcinoma should be included with cervical squamous cell carcinoma as an AIDS-defining illness. HIV-positive patients, particularly AIDS patients, with invasive anal cancers and without effective antiretroviral therapy obtain little benefit and significant toxicity from current radiation therapy and chemotherapy. Initiation of highly active antiretroviral therapy in HIV-positive patients before radiation therapy and chemotherapy are begun may decrease toxicity and improve survival. Additional clinical trials are warranted to test this theory.

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Splenic metastases from colon carcinoma are rare. If present they generally occur in concert with disseminated disease. Six cases have been previously reported. The patient presented here is a 51-year-old black man who presented with an enterocutaneous fistula as a complication from prior pelvic radiation. Workup included an abdominal CT and needle biopsy, which confirmed the splenic metastasis from a sigmoid colon cancer 6 years after the original diagnosis. The patient had an unevenful splenectomy. Although no long-term follow-up data are as yet available splenectomy including removal of hilar lymph nodes appears to be the treatment of choice. A case report and review of the literature are presented.

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NF-kappaB activation is triggered by the degradation of inhibitory proteins, such as I(kappa)B-alpha. I(kappa)B-alpha levels are only transiently lowered since one gene activated by NF-kappaB is I(kappa)B-alpha. We found that I(kappa)B-alpha was replenished rapidly in a human colon cell line (HT-29), even in the presence of degradation-inducing phosphorylation (at serine-32). This finding lead us to hypothesize that posttranscriptional mechanisms were also in place to facilitate I(kappa)B-alpha replenishment. Expression of I(kappa)B-alpha from the constitutive, non-NF-kappaB regulated cytomegalovirus promoter in HT-29 cells showed that TNF-alpha or IL-1beta treatment increased I(kappa)B-alpha levels in the absence of transcriptional activation. The TNF-alpha-induced increase in transgenic I(kappa)B-alpha appeared to result from the stabilization of newly synthesized I(kappa)B-alpha, since this increase was effectively preempted by a proteasome inhibitor (MG132) or by I(kappa)B-alpha stabilization through the deletion C-terminal destabilizing elements (without additive or synergistic effects). Analysis of a hepatoma cell line (Hepa 1-4C7) indicated that the I(kappa)B-alpha stabilization may be constitutive in these cells. NF-kappaB stimuli therefore appear to trigger negative feedback pathways in some cells that terminate a NF-kappaB response by increasing the stability of newly synthesized I(kappa)B-alpha.

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Far forward life-saving surgical care is the mission of an army forward surgical team (FST). Trauma skill maintenance is necessary to complete that mission. A new program has been developed for FST training using the resources of a Level 1 trauma center. We sought to compare the experience of FST surgeons at a major urban trauma center with the yearly trauma experience at an army Level 2 trauma center.General surgeons of the 250th FST prospectively tabulated data for trauma patients during a September 1999 unit deployment to Ben Taub Hospital (Houston, Texas). Data collected included nature and location of injury, hospital admission, and surgical intervention. During 1999, similar data were collected at Madigan Army Medical Center (MAMC) (Ft. Lewis, Washington), home station of the 250th and Level 2 trauma center since November 1998.The FST general surgeons observed 319 injuries. Of those injured, 104 were admitted and 19 underwent urgent operation. Direct participation by FST general surgeons in the operative procedures varied. In 1999, MAMC general surgeons treated 455 trauma victims in direct supervision of Army general surgery residents. Madigan Army Medical Center general surgeons admitted 304 and urgently operated on 57 trauma patients, while 107 patients were transferred to another institution for definitive management of orthopedic and nonoperative neurosurgical injuries.CONCLUSIONS:The volume of trauma surgical cases at MAMC during 1999 was 3 times that seen in the 1-month rotation at Ben Taub. General surgeons performed more trauma and abdominal surgery at MAMC with significantly more direct involvement in patient care and operative procedures. The experience of the 250th FST does not justify trauma sustainment deployments for surgeons from military trauma centers.

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Idiopathic varices of the colon are rare, only 22 cases having been reported in the literature. This case report describes a 27-year-old man with gastrointestinal bleeding from idiopathic colonic varices. The diagnosis was made angiographically. The patient was treated conservatively without surgery and had no recurrence of bleeding in 48 months.

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The transcription factor nuclear factor-kappaB (NF-kappaB) regulates genes that can influence cell proliferation, apoptosis, and inflammatory responses. Since these events can contribute to carcinogenesis, we examined the expression of NF-kappaB inhibitory proteins (IkappaBs) in normal and transformed colonic epithelial cells. Immunohistochemical analysis of the mouse colon revealed a high level of IkappaBbeta expression in epithelial cells relative to the rest of the tissue, whereas IkappaBalpha was found primarily in cells of the lamina propria. Mouse colon tumors showed a similar cell-specific staining pattern. Immunoblot analysis of IkappaBbeta from mouse colonocytes and the human HT-29 colon cancer cell line indicated that most of the IkappaBbeta in these cells was similar to the C-terminal-truncated IkappaBbeta2 isoform. Cell fractionation studies were consistent with IkappaBbeta being a major regulator of p65-p50 NF-kappaB complexes in HT-29 cells. Interestingly, two larger proteins specifically recognized by IkappaBbeta antibodies (p106 and p112) were found in HT-29 cells and in colon tissue of carcinogen-exposed mice. The p106 and p112 proteins bound to NF-kappaB, and their levels changed during the transient interleukin-1beta activation of NF-kappaB in HT-29 cells. Evidence was obtained indicating that p106 and p112 are stably ubiquitinated forms of IkappaBbeta. We propose that deficiencies in the proteasomal degradation of IkappaBbeta lead to p106 and p112 accumulation, which in turn alter NF-kappaB regulation in colon cancer cells.

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PURPOSE: The purpose of this study was to evaluate the effectiveness of ketorolac combined with local anesthetics for anorectal surgery. METHODS: From June 1998 through March 1999, 123 outpatients undergoing anorectal surgery were entered into a prospective, randomized, double-blinded study involving three treatment groups. All patients received intravenous sedation consisting of fentanyl and a propofol infusion, with a local anesthesia mixture of lidocaine, bupivacaine, and bicarbonate. Group A (41 patients) received placebo (saline) injections. Group B (41 patients) received 60 mg of intravenous ketorolac at the onset of the procedure, and Group C (41 patients) received 60 mg of ketorolac mixed with the local anesthetic. Data were analyzed using analysis of variance and chi-squared tests. RESULTS: All groups had similar demographic characteristics and operative procedures. Twenty-nine of the 123 patients were human immunodeficiency virus-positive. There was no difference in operative or anesthesia time. Anesthesia and fluids given were similar in across groups. A significantly higher percentage of Group A patients had pain (34 percent) and required additional oral analgesia (20 percent) in the Day Surgery Unit. Only 5 percent of Group B and Group C patients complained of pain, with oral analgesics given to 2 percent of Group B and none in Group C. Voiding difficulties were more common in Group A patients, one patient requiring catheterization. CONCLUSION: The addition of ketorolac (60 mg), either intravenous or injected with local anesthetics, reduces voiding problems and significantly decreases postoperative analgesic requirements in outpatients undergoing anorectal surgery.

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We report the case of a 56-year-old man with episodic right lower quadrant abdominal pain. Preoperative evaluation included computed tomography (CT) showing a right lower quadrant phlegmon consistent with cecal diverticulitis or appendicitis. The patient was treated with a short course of bowel rest and antibiotics. Four weeks later, he had an appendectomy. The patient was found to have chronic appendiceal diverticulitis and recovered uneventfully. Histopathologic studies revealed herniated mucosa through the muscular layer associated with chronic inflammation and marked fibrosis. These findings represent appendiceal diverticulitis. Diverticulosis of the appendix is believed to be uncommon and roentgenologic diagnosis of appendiceal diverticular disease is rarely made. We discuss the diagnosis and CT findings of appendiceal diverticulitis and present a thorough review of the literature.

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BACKGROUND AND OBJECTIVE: Primary lymphoma of the anus is an extremely rare problem. In patients with the Acquired Immune Deficiency Syndrome (AIDS), there is a marked increase in gastrointestinal non-Hodgkin's lymphomas (NHL). The aim of this study was to evaluate the outcome of patients with anorectal NHL and AIDS. METHODS: Over an 18-year period, we identified 6 patients with AIDS and primary anorectal NHL. Five were male. All were high-grade B-cell lymphomas and half showed systemic "B" symptoms. Patient's mean CD4 count was 93 (range 8 to 201). RESULTS: The average life span for those with "B" symptoms was 6.7 months and 16 months for those without symptoms. No benefit was shown from radiation or chemotherapy in those with "B" symptoms. Younger patients and those without systemic constitutional symptoms of lymphoma do better. One patient without "B" symptoms was able to tolerate his radiation and chemotherapy and is disease free at 10 months. CONCLUSION: Despite traditional non-Hodgkin's lymphoma treatment regimens, our AIDS patients (and those examined in a review of the pertinent literature) with anorectal NHL and "B" symptoms have a poor prognosis. For those without "B" symptoms and who can tolerate the therapy, NHL remission may be obtained.

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BACKGROUND: Although the syndrome of familial adenomatous polyposis is well known, sporadic patients with multiple polyposis are rare. There are no known syndromes associated with hyperplastic polyposis. In our search of the English surgical literature, we find no reference to a hyperplastic-adenomatous polyposis syndrome. STUDY DESIGN: Over a 3-year period, we identified six patients ages 41 to 75 (mean age 61) with 50 to 100 hyperplastic polyps associated with adenomas. RESULTS: Most of the hyperplastic polyps were found in the left colon and the largest ranged in size from 6 mm to 18 mm. The larger polyps were clinically indistinguishable from adenomas. Three of our six patients had invasive cancer of the proximal colon. All tumors were confined to the bowel wall. There was a family history of colon cancer in only one patient and no family history of polyposis. CONCLUSION: These patients differ from previously described patients with polyposis syndromes; hyperplastic-adenomatous polyposis syndrome (HAPS) occurs in an older population with no family history of polyposis, has fewer polyps, most of which are hyperplastic, and is strongly associated with adenocarcinoma of the colon. In this series, we describe a previously unreported hyperplastic-adenomatous polyposis syndrome.

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BACKGROUND: We reviewed our experience with stereotactic core needle breast biopsy (SCNBB) for accuracy, complication rate, and staging profile of malignancies diagnosed. METHODS: Since March 1993, 530 stereotactic biopsies were performed. Of these, 25 cases underwent stereotactic core needle biopsy with subsequent wire-guided biopsy. RESULTS: In 25 patients with stereotactic and open biopsy, there was an accuracy for SCNBB of 96%. The number of biopsies rose from 100 to 250 biopsies annually, with an equivalent pre-test positive predictive value for mammography (17% to 19% historical versus 20% with SCNBB). The total number of de novo cancer diagnoses have increased from a mean of 57 to a mean of 71 annually. The percentage of tumors in situ, stage I or stage II, has increased from 60% to 69%. CONCLUSIONS: Stereotactic core needle biopsy combines a high accuracy with a low complication rate. Its aggressive application for tissue diagnosis in suspicious nonpalpable mammographic lesions has increased the proportion of early (in situ and T1 or T2) tumors discovered, and increased the total number of breast cancers diagnosed.

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