Gastrointestinal Stromal Tumors: A Clinicopathological and Immunohistochemical Study of 65 Cases.

OBJECTIVE: The clinical behavior of gastrointestinal stromal tumors is divergent. The aim of the present study was to define the clinicopathological features that determine the patient's outcome. MATERIAL AND METHOD: Sixty-five gastrointestinal stromal tumors were reviewed with their histological, immunohistochemical and clinical features and compared with their clinical outcome statistically. RESULTS: Tumors were located in the stomach (n=39, 60%), small intestine (n=22, 33.8%) and large intestine (n=4, 6.2%). Immunohistochemically, CD 117 positivity was found in 90.8%, whereas CD34, Smooth muscle actin, Desmin and S100 positivity was found in 73.3%, 61.7%, 11.7% and 28.3% of tumors respectively. All six ''CD 117-negative'' cases expressed DOG-1. The mean Ki-67 proliferation index was 8.69%±12.76. Liver metastasis was detected in seven cases. A significant association was detected between decreased mean survival time and increased tumor size (p < 0.001), large bowel localization (p=0.047), mitosis (p < 0.001), the presence of necrosis (p=0.001), metastasis (p=0.033), Ki-67 proliferation index (p=0.002) and risk category (p < 0.001). CD 34 positivity was mostly seen in the stomach (p=0.001), and CD 34 positive tumors had longer overall survival (92.85.±5.77 months versus 67.21±13.68 months) (p=0.046). Higher Ki-67 proliferation index (≥6%) was also correlated with the presence of metastases (p=0.015). CONCLUSION: Our study indicates that in addition to well-known risk factors such as increased tumor size, high mitotic activity and metastasis; higher Ki-67 proliferation index, the presence of necrosis, and CD34 negativity also correlate with shorter survival time.

Are carriers for MEFV mutations "healthy"?

OBJECTIVE: We aimed to compare whether carriers for the MEFV mutations display an increase or decrease in certain features. We compared the frequency of a number of inflammatory symptoms and diseases in carriers and a control population. METHODS: A questionnaire was designed to be applied to parents of children with FMF and a control group of parents. Clinical features and some diseases including the frequency of febrile episodes, abdominal pain, arthralgia, prophylaxis with penicillin, acute rheumatic fever, rheumatoid arthritis, vasculitis, spondyloarthropathy, urinary tract infection, asthma, allergy, irritable bowel disease, appendectomy and tonsillectomy were inquired. 676 parents of 440 children with FMF were surveyed in this study. Controls (n: 774) were selected as parents of healthy children. RESULTS: The presence of febrile episodes more than four per year, arthralgia, past diagnosis for acute rheumatic fever, rheumatoid arthritis and prophylaxis of penicillin, acute rheumatic fever, and rheumatoid arthritis were significantly higher in asymptomatic parents for the MEFV mutations compared to controls. The frequency of allergy was found to be significantly lower in the asymptomatic parents as compared to controls. There was no significant difference at the frequency of urinary tract infection and tonsillectomy between the parents of the patents and controls. CONCLUSIONS: We suggest that one MEFV mutation may indeed be conferring a heightened inflammation as suggested by the increased frequency in inflammatory symptoms. The carrier status for MEFV mutations seem to be unique, in that they cause an alteration in the state of "health".

Intralesional treatments for hypertrophic scars: comparison among corticosteroid, 5-fluorouracil and botulinum toxin in rabbit ear hypertrophic scar model.

OBJECTIVE: Different treatment modalities have been used either alone, or in combination to achieve an optimum improvement for hypertrophic scars. Intralesional injections of corticosteroids and 5-fluorouracil are among the most commonly used treatments. Recently, botulinum toxin is proposed as a new treatment option. In this study, it is aimed to compare the efficacies of intralesional triamcinolone acetonide, 5-fluorouracil and botulinum toxin-A for hypertrophic scars. In order to minimize the variables affecting scar formation, standardized wounds in rabbit ear hypertrophic scar model was used. MATERIALS AND METHODS: Four surgical wounds were created on both ears of eight rabbits. Injections to be compared (triamcinolone acetonide, 5-fluorouracil, botulinum toxin-A and control) are administered intralesionally to established scars on day 30. Scars were harvested on day 60 for morphometric analysis including hypertrophic index, fibroblast density, and relative collagen density. RESULTS: Triamcinolone acetonide and 5-fluorouracil injections decreased hypertrophic indexes significantly compared to botulinum toxin-A and control group. However, only 5-fluorouracil was effective to reduce fibroblast counts significantly. No statistically significant differences were found between the treatment groups in terms of collagen index. CONCLUSIONS: According to the results of our study, triamcinolone acetonide and 5-fluorouracil are comparatively effective as monotherapy, but botulinum toxin-A was not effective on established hypertrophic scars.

The genetic basis of autosomal dominant familial Mediterranean fever.

Familial Mediterranean fever (FMF) is classically an autosomal recessive periodic inflammatory disease occurring in Mediterranean and Middle Eastern populations. It is caused by mutations affecting both alleles of MEFV, a gene that encodes pyrin (marenostrin), an uncharacterized neutrophil protein. Occasional reports of autosomal dominant FMF have often been discounted, on the basis that asymptomatic FMF carriers are common in certain populations, and give rise to pseudo-dominant inheritance. We performed comprehensive MEFV genotyping in five families in whom FMF appeared to be inherited dominantly. Transmission proved to be pseudo-dominant in two cases, but true dominant inheritance of FMF with variable penetrance was supported by the genotyping results in the other three families. The disease in these cases was associated with heterozygosity for either pyrin DeltaM694 alone or the compound pyrin variant E148Q/M694I, the latter occurring in two unrelated families. Complete MEFV sequencing failed to identify any coding region abnormality in the other allele in any of these cases, and, in the largest kindred, single-allele disease transmission was further supported by analysis of silent single nucleotide polymorphisms, which proved that affected individuals had at least three different complementary alleles. Studies of two further unrelated British patients with FMF associated with simple heterozygosity for pyrin DeltaM694 were also consistent with autosomal dominant inheritance. The clinical features of dominantly inherited FMF were absolutely typical, including AA amyloidosis in a patient with pyrin DeltaM694. These findings extend the spectrum of FMF, and suggest that the methionine residue at position 694 makes a crucial contribution to pyrin's function, and that a 50% complement of normal pyrin activity does not prevent susceptibility to FMF.

Elderly hypertensive patients: are they adequately treated?

To better understand the scope and importance of hypertension in elderly persons, we analysed 551 outpatients, > or = 65 years of age. Arterial BP values > 160 mmHg systolic or 90 mmHg diastolic were documented in 233 cases (42.29% of total). Among this hypertensive group of patients, 174 of them (74.68%) were chronic cases and 59 patients (25.32%) were newly diagnosed. Only 39 of the 174 chronic patients were receiving adequate treatment (22.41%), 87 patients were not receiving any treatment (50%) and 40 others lacked information about previous treatments (23%). Apart from the 35 patients (15.02%) who were treated with salt-restricted diet only, we prescribed antihypertensive drugs to all the remaining 198 patients (84.98%): diuretics (41.92%), calcium antagonists (33.33%), beta-blockers (17.86%), ACE inhibitors (15.66%) and various other drugs (8.1%), with good patient compliance and minimal side-effects. Of the 233 hypertensive patients, 64.81%, had accompanying health problems such as cerebrovascular disease (17.95%), diabetes (16.67%), coronary artery disease (16.24%) and cancer (7.27%). It is concluded that hypertension among the elderly is an important and underestimated part of an already complicated health picture of this expanding population of modern society.

Increased frequency of familial Mediterranean fever in Central Anatolia, Turkey.

OBJECTIVE: It has been observed that familial Mediterranean fever is more prevalent among people coming from central Anatolia in Turkey. To test this observation the frequency of FMF was investigated by afield survey in Sivas, a city located in central of Turkey. METHODS: The survey was conducted in a cohort of 4809 persons selected by systematic sampling from 2 districts of Sivas, with a total population of 83,274. Face to face interviewing was done with registered households using a standard questionnaire developed to screen FMF A second interview was conducted by a rheumatologist and an internist of those individuals who were regarded to have possible FMF. RESULTS: The suspicion of FMF emerged in the cases of 46 individuals during the survey and 36 were interviewed for a second time. FMF was diagnosed in 10 cases. Only one had a previous diagnosis of FMF. The overall frequency of FMF among a cohort of 3,948 inhabitants of Sivas was 1/395 (0.25%). CONCLUSION: This study indicates that the prevalence of FMF in Sivas may be higher than that in general Turkish population, which has been reported to be 0.1%.

Levels of interleukin-6 (IL-6) and its soluble receptor (sIL-6R) in familial Mediterranean fever (FMF) patients and their first degree relatives.

OBJECTIVE: Familial Mediterranean Fever (FMF) is a hereditary disease characterized by recurrent inflammatory attacks. A subclinical inflammation may persist in periods between the attacks and heterozygotes may have higher than normal levels of acute phase proteins. We investigated the levels of interleukin-6 (IL-6) and its soluble receptor (sIL-6R) in FMF patients and their obligatory carrier relatives. METHODS: Serum levels of IL-6 and sIL-6R were measured during acute attacks (n = 18) and in attack-free FMF patients (n = 26), obligatory carriers of FMF (n = 17) and normal controls (n = 11). RESULTS: The median levels of IL-6 were significantly higher (45.71 pg/ mL, p = 0.001) during acute attacks of FMF only, and were normal (0.01 pg/ mL) in the other groups studied. There was no statistically significant difference in the median sIL-6R values between any of the groups (p = 0.22). CONCLUSION: IL-6 was extremely elevated during FMF attacks but could not detect hypothetical "subclinical" inflammation during attack-free intervals or in the heterozygote relatives of patients. Serum levels of sIL-6R were comparable in all four groups.

The effect of interferon alpha administration on acute attacks of familial Mediterranean fever: A double-blind, placebo-controlled trial.

BACKGROUND: About a quarter of familial Mediterranean fever (FMF) patients are partially or totally resistant to colchicine. A previous observation reported that acute attacks may be shortened by administration of interferon alpha (IFN). OBJECTIVE: We designed a double-blind, placebo-controlled trial to test our initial observations of a beneficial response with IFN in FMF attacks. METHODS: We treated 34 acute abdominal attacks with IFN 5 million IU or placebo sc in the early phase of the attack. Leucocytes, thrombocytes, the erythrocyte sedimentation rate, fibrinogen, C-reactive protein (CRP), serum amyloid A protein (SAA), haptoglobin, transferrin, IL-1beta and TNF-alpha were measured at hours 0, 6, 12, 24 and 48. RESULTS: The median time to recovery in those treated with IFN and placebo was not significantly different, while the leucocytosis and high levels of fibrinogen were significantly more prolonged in placebo-treated patients. CRP and SAA were extremely elevated and peaked at 24h, remaining less marked in the IFN-treated patients but the difference was not statistically significant. Observations regarding the other parameters were unremarkable. CONCLUSIONS: Although there were some clues indicating a depressed inflammatory response with IFN, we could not demonstrate a definitive effect of this agent in this double-blind trial. The drug may suppress the acute inflammation of FMF only if administered at the earliest phase. CRP and SAA may be more sensitive indicators of an attack than ESR or fibrinogen.

A case of recurrent pancreatitis due to hyperlipidemia misdiagnosed as familial Mediterranean fever.

Familial Mediterranean fever (FMF) is prevalent among Arabic, Turkish, Armenian, and Jewish people and it must always be considered in the differential diagnosis of patients from these ethnic groups presenting with recurrent abdominal pain with fever. In cases of fever and recurrent abdominal pain, acute pancreatitis is an important clinical condition, which should be considered in the differential diagnosis. Serum amylase concentration in acute pancreatitis is usually more than three times the upper limit of normal. However, in recurrent pancreatitis secondary to hypertriglyceridemia, serum amylase levels, for reasons that are not well understood, may be normal or mildly elevated. Recurrent pancreatitis secondary to hypertriglyceridemia may thus pose a problem in the differential diagnosis and may lead to an erroneous diagnosis of FMF. Measurement of serum triglyceride along with amylase levels should be required for a suspected diagnosis. Computerized examination of the abdomen may need to be undertaken to exclude acute pancreatitis in the presence of hypertriglyceridemia since serum amylase levels may be normal or slightly elevated.

Coexistence of familial Mediterranean fever with sacroiliitis and Behçet's disease: a rare occurrence.

Familial Mediterranean fever (FMF) and Behçet's disease are relatively rare but may still coexist in the same patient. Sacroiliitis is another feature whose significance is controversial in either of the diseases. We report a case of longstanding FMF with sacroiliitis who later developed typical characteristics of Behçet's disease. Although occurrence by chance cannot be ruled out, this unusual patient may enhance the claims that FMF and Behçet's disease have common aetiopathogenetic mechanisms. It would be appropriate to include this coexistence in the list of differential diagnoses of the two diseases.

A case of cerebral tuberculosis after liver transplant and literature review.

The risk of active tuberculosis is high in solid-organ recipients. We evaluated the clinical presentation of tuberculosis. Pulmonary locations were the most frequent, and extrapulmonary locations were rarely seen. Among extrapulmonary sites, intracranial tuberculosis is rare, with a few case reports reported in the literature. We report a case of 27-year-old man, who received deceased-donor liver transplant due to hepatitis B virus-related chronic liver failure. One month after the liver transplant, neurologic symptoms developed, then he had attacks of tonic-clonic convulsions. Cerebral stereotactic needle biopsy of left temporal lobe was performed. Histopathologically gliosis, rare lymphocyte infiltration, and epithelioid histiocytes were seen. Histochemical staining by Ziehl-Neelsen stain noted acid-fast resistant bacillus. The case was diagnosed as granulomatous inflammation which led to tuberculosis. In addition to antituberculosis therapy, he was given antiviral therapy for prophylaxis. During therapy, reactivation of hepatitis B virus was noted, and the recurrent diseases of hepatitis B virus-related viral hepatitis was diagnosed on serial biopsies. Ten months after transplant, he died from liver failure. Tuberculosis is a serious opportunistic infection in transplant recipients. The incidence of Mycobacterium tuberculosis infection in organ transplant recipients worldwide ranges from 0.35% to 15%. In nonrenal transplant, rejection within 6 months before the onset of tuberculosis and type of primary immunosuppressive regimen were predictors of tuberculosis infection occurring 12 months after transplant. The diagnosis and effective management of tuberculosis after transplant warnings recognition of the epidemiologic and clinical characteristics of tuberculosis in transplant recipients.

Posttransplant lymphoproliferative disorder after liver and kidney transplant.

OBJECTIVES: We evaluated posttransplant lymphoproliferative disorder after solid-organ transplant. MATERIALS AND METHODS: All 2224 solid-organ transplant recipients who underwent transplant between 1985 and 2013 were included. Clinicopathological findings were examined, and all patients with posttransplant lymphoproliferative disorder were reclassified to World Health Organization 2008 lymphoma classification. RESULTS: Only 27 of 2224 patients developed posttransplant lymphoproliferative disorder. The incidence of posttransplant lymphoproliferative disorder was 3.3-fold higher in children than in adults. The mean interval between transplant and diagnosis of posttransplant lymphoproliferative disorder was 65 months. Patients with tacrolimus were associated with a shorter posttransplant lymphoproliferative disorder development time compared with cyclosporine patients. Epstein-Barr virus-encoded small RNA positive showed shorter time for development of posttransplant lymphoproliferative disorder compared with Epstein-Barr virus-encoded small RNA negative patients. The risk of developing posttransplant lymphoproliferative disorder within the first year of transplant was higher in patients under tacrolimus protocol compared with patients under cyclosporine. Of 27 patients, 4 showed early lesion and 23 patients showed monomorphic posttransplant lymphoproliferative disorder. The development of T-cell monomorphic posttransplant lymphoproliferative disorder was significantly late compared with patients with B-cell monomorphic posttransplant lymphoproliferative disorder. Eight patients died at 38 ± 50 months after posttransplant lymphoproliferative disorder diagnosis. Four patients with early type posttransplant lymphoproliferative disorder were alive, and 3 of 4 patients with T-cell monomorphic posttransplant lymphoproliferative disorder died shortly after diagnosis. Five of 19 patients with B-cell monomorphic posttransplant lymphoproliferative disorder died at a mean 29 ± 18 months. A significant difference was found between the histologic types regarding patient survival. A significant difference was found between the Epstein-Barr virus-encoded small RNA positive and Epstein-Barr virus-encoded small RNA negative patients regarding mean survival time. CONCLUSIONS: To decrease the incidence of posttransplant lymphoproliferative disorder, risk factors should be evaluated and new approaches must be derived for prophylaxis, diagnosis, and treatment.

Nonmelanoma skin cancer after kidney transplant.

OBJECTIVES: Solid-organ transplant recipients have a high risk of developing nonmelanoma skin cancers. This study sought to determine the incidence of skin cancer and identify possible risk factors for skin cancer in kidney transplant recipients. MATERIALS AND METHODS: Nonmelanoma skin cancer was diagnosed and confirmed with histology in 33 of 1275 kidney transplant recipients (2.6%). Demographic and clinical findings were reviewed retrospectively. RESULTS: Nonmelanoma skin cancers included squamous cell carcinoma in 10 patients (30%), basal cell carcinoma in 9 patients (27%), Kaposi sarcoma in 9 patients (27%), squamous cell carcinoma in situ in 3 patients (9%), and cutaneous lymphoma in 2 patients (6%). The ratio of squamous cell carcinoma to basal cell carcinoma was 1.1:1. The mean time from transplant to skin cancer diagnosis was 65 ± 55 months (range, 0-180 mo). Immunosuppressive therapy was based on cyclosporine in 22 patients (67%), tacrolimus in 8 patients (24%), and combination therapy (cyclosporine and azathioprine) in 3 patients (9%). CONCLUSIONS: Nonmelanoma skin cancer is an important clinical problem in kidney transplant recipients. Interventions that may benefit kidney transplant recipients may include intensive patient education, protection against sun exposure, and dermatologic screening programs.

Acrokeratoelastoidosis treated with the erbium:YAG laser.

Acrokeratoelastoidosis is a rare skin disorder characterized by grouped, small, firm, translucent papules distributed on the margins of the hands and feet. We report a 21-year-old white patient with acrokeratoelastoidosis in whom Er:YAG laser surgery was carried out, resulting in a slight post-treatment improvement of the disease with slight flattening of the lesions. No clinical recurrence of the lesions developed during the 6 months of follow-up. We suggest that Er:YAG laser surgery of acrokeratoelastoidosis may be considered as a treatment option for this rare disease; however, patients should be informed of the limited clinical improvement obtained with this treatment.

Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations.

OBJECTIVE: To prospectively monitor inflammatory activity over a prolonged period in a cohort of Turkish patients with FMF, their healthy relatives and healthy controls and to relate this to their MEFV genotypes. METHODS: 43 patients with FMF and 75 of their asymptomatic relatives underwent fortnightly assessments and venesection for measurement of CRP and SAA over 5 months. 50 unrelated healthy population matched controls were also studied. MEFV genotyping was performed on all participants and comparisons were made between the different groups. RESULTS: Paired MEFV mutations were detected in 84% of FMF patients and single mutations in 12%. Substantial acute phase reactivity was seen among the patients with FMF during attacks (median SAA 693 mg/l, CRP 115 mg/l). Between attacks there was also some inflammatory activity (median SAA 6 mg/l, CRP 4 mg/l). Among healthy controls 16% were heterozygotes for MEFV mutations and 4% had two mutations. As expected there was a substantial carrier rate among healthy relatives with mutations detected in almost 92%. Asymptomatic MEFV heterozygotes had elevated acute phase proteins compared to wild type subjects. CONCLUSION: Substantial sub-clinical inflammation occurs widely and over prolonged periods in patients with FMF, indicating that the relatively infrequent clinically overt attacks represent the 'tip of the iceberg' in this disorder. Both basal and peak acute phase protein concentrations were greater in MEFV heterozygotes than in wild-type controls, regardless of mutation demonstrating a 'pro-inflammatory' phenotype among FMF carriers. Upregulation of the acute phase response among carriers of FMF may augment their innate host response and contribute to better resistance to infection.

The efficacy of interferon alpha on colchicine-resistant familial Mediterranean fever attacks: a pilot study.

About a quarter of familial Mediterranean fever (FMF) patients have recurrent painful attacks of polyserositis despite regular colchicine treatment. There is no known alternative drug for colchicine-resistant cases. We had previously observed a patient with FMF whose painful attacks disappeared during the 6 month period of interferon alpha (IFN) treatment for his chronic hepatitis B. The objective of the present study was to investigate the possible beneficial effect of IFN on these episodes. Twenty-one consecutive attacks in seven adult patients with FMF were treated at early onset with IFN, the dosage being 3-10 million I U s.c. Eighteen of the 21 attacks could be halted in a mean time of 3.05 h, while the intensity of abdominal pain remained very low. Observed side-effects were generally mild and acceptable. IFN may be a useful adjunct for the treatment of colchicine-resistant attacks in FMF patients.

Phase I study with the DNA sequence-specific agent adozelesin.

Adozelesin, a synthetic analog of the antitumor antibiotic CC-1065, is a novel cytotoxic agent which inhibits DNA synthesis by binding to the minor groove of the DNA helix. Preclinical studies have shown a broad spectrum of activity against a variety of murine and human tumor xenograft models. We conducted a phase I study of adozelesin to (i) determine a recommended dose for phase II testing using a 10 min i.v. infusion, (ii) characterize the toxic effects of the drug using this schedule and (iii) document any antitumor activity observed. Adozelesin was administered as an i.v. infusion every 6 weeks. CBC and biological parameters were performed weekly. The starting dose of 10 microg/m2, corresponding to 1/30 the mouse equivalent lethal dose, was escalated, according to a modified Fibonacci scheme, until dose-limiting toxicity was encountered. Forty-seven adult patients with solid malignancies were entered in the study. Successive dose levels used were 10, 20, 33, 50, 70, 105, 120, 150 and 180 microg/m2. The main toxic effect was myelosuppression, which was dose limiting. The maximally tolerated dose was defined as 180 microg/m2. A minor response with a 4 month duration was reported in one previously treated patient with melanoma. We conclude that the recommended phase II dose of adozelesin given as a 10 min infusion is 150 microg/m2, repeated every 4 weeks.