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First Manifestation (first + manifestation)
Selected AbstractsThe pathology of hypertrophic cardiomyopathyHISTOPATHOLOGY, Issue 5 2004S E Hughes Sudden cardiac death (SCD) is devastating at any age, but even more so when the individual affected is young and asymptomatic, and the death is entirely unexpected. SCD is a catastrophic complication of hypertrophic cardiomyopathy (HCM) and may be the first manifestation of this disease. HCM is an inherited intrinsic disease of the myocardium characterized by left ventricular hypertophy without chamber dilatation, in the absence of either a systemic or other cardiac disease, which may cause a similar magnitude of hypertrophy. HCM may be a clinically silent disease. Indeed, the pathologist may be the first to encounter a case of HCM at autopsy. HCM has wide-ranging implications for affected families, who will require cardiac screening and genetic counselling even if mutations are not known. Therefore, prompt and accurate diagnosis of HCM is vital. This review article will focus on the pathological diagnosis of HCM, recent advances in the genetics of this disease, and common pitfalls which may arise, leading to diagnostic uncertainty. [source] Role of infections in the manifestation or reactivation of inflammatory bowel diseasesINFLAMMATORY BOWEL DISEASES, Issue 3 2002Dr. Andreas Stallmach Abstract The etiology of inflammatory bowel disease (IBD) is unknown. In addition to genetic and environmental factors, microorganisms have been discussed as possibly playing an important role. Recent reports in the literature do not suggest that a specific persistent infection causes IBD, but indicate that enteric pathogens could cause initial onset of IBD and are associated with reactivation of quiescent disease. Despite their self-limited character, these infections initiate a cascade of inflammatory events leading to chronic, relapsing disease in a genetically susceptible host ("hit-and-run" hypothesis). Epidemiological and microbiologic studies suggest that enteropathogenic microorganisms play a substantial role in the clinical initiation and relapses of IBD. However, similar to traveler's diarrhea, the frequency of infections in the first manifestation and in relapses of IBD is probably understated, due to the problems in detecting enteric pathogens. Thus microbiologic screening is helpful in patients with flares of IBD for optimal medical treatment. [source] Psychiatric disorder as a first manifestation of cancer: A 10-year population-based studyINTERNATIONAL JOURNAL OF CANCER, Issue 12 2009Michael E. Benros Abstract To investigate the possibility that psychiatric symptoms could be caused by a yet undetected cancer or be part of a paraneoplastic syndrome, nationwide population-based registers were linked including the Danish Psychiatric Central Register and the Danish Cancer Registry. Data were analysed as a cohort study using survival analysis techniques and incidence rate ratios (IRRs) were used as measures of relative risk. A total of 4,320,623 persons were followed in the 10-year period 1994,2003, resulting in 37,581,600 person-years at risk, 202,144 persons with a first-time psychiatric contact, and 208,995 persons diagnosed with cancer. During the first month after a first-time psychiatric contact, the incidence of all forms of cancer was elevated; IRR: 2.61 (95% CI, 2.31,2.95). Particularly the incidence of brain tumours was elevated; IRR: 18.85 (95% CI, 14.52,24.48), but also the incidence of lung cancer; IRR: 2.98 (95% CI, 2.16,4.12), and especially small-cell lung cancer; IRR: 6.13 (95% CI, 3.39,11.07) was elevated. The elevated IRR for most cancers decreased towards unity within the first 3 months, except for brain tumours, for which the IRR remained significantly elevated during the first 9 months. One of every 63 patients above 50 years of age was diagnosed with malignant cancer within 1 year of first-time psychiatric contact. These results indicate an increased incidence of cancer, especially for brain tumours and small-cell lung cancer, in the first months after a first-time contact to a psychiatric hospital. Clinicians should be aware that first-onset psychiatric symptoms could be a sign of a yet undetected cancer. © 2009 UICC [source] Cutaneous metastasis: a clinical, pathological, and immunohistochemical appraisalJOURNAL OF CUTANEOUS PATHOLOGY, Issue 6 2004Sadia Saeed Background:, Cutaneous tumor metastasis may be the first manifestation of cancer, but more often is a harbinger of advanced disease that portends an ominous prognosis. All skin accessions over the past 10 years from a large Veterans Administration (VA) hospital were reviewed. Methods:, Archived histories, glass slides, and the immunohistochemical battery (IHC), were assessed to determine diagnostic accuracy. Results:, Of the 100,453 cases reviewed, there were a total of 77 cases (75 males and 2 females) of cutaneous metastasis from the lungs (28.6%), metastatic melanoma (18.2%), gastrointestinal tract (14.2%), genitourinary tract (10.4%), head and neck (9.1%), hematologic (5.2%), breast (5.2%), and miscellaneous (<2%). Metastasis represented the first indication of an internal malignancy in 7.8% of cases. The cutaneous sites of involvement included the head and neck (28%), the trunk (40%), the extremities (18%), and multiple sites (14%). The age range was 38,83 years, with a mean of 62 years. The average time interval between diagnosis of internal malignancy and cutaneous presentation was 33 months (range: <1 month,22 years), and the average survival following diagnosis was 7.5 months (range: <1 month,8 years). In a cohort of subjects, a truncated immunohistochemical battery consisting of CK-7, CK-20, and S-100 was consistent with the expected staining pattern of the primary source of cutaneous metastasis in 83.33% of the patients. Conclusions:, Excluding the potential for age and gender bias in this study conducted in a VA setting, cutaneous metastases represent an uncommon, deadly, and late-developing occurrence in many patients. Compared with previous studies, lung carcinoma remains the most common of the cutaneous metastases, with a relative rise in the incidence of metastatic melanoma. The immunohistochemical battery of CK-7, CK-20, and S-100 is a helpful adjunct in narrowing the differential diagnosis of the primary site of a large proportion of cutaneous metastases, particularly tumors with an epithelioid appearance such as carcinomas and melanomas. [source] Non-hematopoietic cutaneous metastases in children and adolescents: thirty years experience at St. Jude Children's Research HospitalJOURNAL OF CUTANEOUS PATHOLOGY, Issue 10 2000W. A. Wesche Background: The spectrum of cutaneous metastasis of non-hematopoietic neoplasms in the pediatric population is not well documented. We report the histologic diversity of this unusual process over a 30-year period at a tertiary care center for pediatric malignancy (St. Jude Children's Research Hospital, Memphis, TN, USA). Methods: Of 1,971 pathology accessions which included histologic material on skin (1,604 surgical cases and 367 autopsy cases) we found 40 cases (2% of total skin accessions) coded for metastatic non-hematopoietic malignancy. Results: The patients (n=34) ranged in age from 1 month to 20 years (mean=9.8 years) and had a male:female ratio of 1:1. The histologic diagnoses were as follows: rhabdomyosarcoma NOS (6 cases), embryonal rhabdomyosarcoma (4 cases), alveolar rhabdomyosarcoma (4 cases), neuroblastoma (8 cases), osteosarcoma (2 cases), choriocarcinoma (2 cases), peripheral neuroepithelioma or Ewing's sarcoma (2 cases), malignant rhabdoid tumor (1 case), paraganglioma (1 case), nasopharyngeal carcinoma (1 case), sarcoma NOS (1 case), colon adenocarcinoma (1 case), and malignant melanoma (1 case). Conclusions: Cutaneous or subcutaneous metastasis of non-hematopoietic malignancies in children and adolescents is a rare occurrence but in a high percentage of cases may be the first manifestation of disease. The tumors most likely to metastasize to the skin in children are rhabdomyosarcoma and neuroblastoma and they are more likely than adult malignancies to disseminate to multiple distant sites. [source] Incidence and odds ratio of appendicitis as first manifestation of colon cancer: A retrospective analysis of 1873 patientsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 11 2006Hung-Wen Lai Abstract Background and Aim:, Obstruction of the lumen of the appendix is the major cause of appendicitis. Tumors could obstruct this lumen and cause appendicitis in the elderly. The association between appendicitis and colon cancer has not been sufficiently investigated, and this study was designed to clarify this association. Methods:, This was a retrospective study. Patients diagnosed with acute appendicitis from January 1998 to December 2003 at the Taipei Veterans General Hospital were surveyed. Patients found to have colon cancers immediately or subsequently after appendectomy were included and analyzed. Results:, A total of 1873 patients were diagnosed as having appendicitis of whom 16 were found to have colon cancer. The incidence of appendicitis associated with colon cancer was 0.85%. The time from appendectomy to the recognition of colonic cancer was at a median delay of 5.8 months. From the Taiwan Cancer Research Annual Report, the incidence of colon cancer was 31.91/100 000 in the year 2000. The odds ratio of colon cancer incidence had a 38.5-fold increase among patients older than 40 with acute appendicitis. Conclusions:, In patients over 40 years who present with symptoms of acute appendicitis the possibility of a coexistent colonic neoplasm should always be kept in mind. These patients should undergo colonoscopy 6 weeks after surgery to exclude the possibility of a coexistent colorectal cancer. [source] Follicular cysts and hyperkeratoses as first manifestation, and involvement of the central nervous system as late manifestation of mycosis fungoidesJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 6 2005PCM Van De Kerkhof [source] Impact of environmental and hereditary risk factors on the clinical manifestation of thrombophilia in homozygous carriers of factor V:G1691AJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 3 2004S. Ehrenforth Summary.,Background:,Limited data exist on the clinical manifestations of homozygous factor (F)V:G1691A mutation (FV Leiden) and the impact of environmental and genetic risk factors. Objectives:,To assess the contribution of these factors on the thrombophilic phenotype. Patients and methods:,In a retrospective multicenter cohort study 165 individuals with homozygous FV:G1691A mutation, of whom 129 had previous venous thromboembolism (VTE), were included. To study the role of environmental risk factors, patients were compared by the use of a standardized questionnaire to 165 sex- and age-matched individuals (reference group A); of these, two had previous VTE. To assess the role of genetic risk factors, factor (F)II:G20210A and MTHFR:C677T were determined in individuals homozygous for FV:G1691A and in 177 healthy individuals without previous VTE (reference group B). Results:,The first VTE occurred significantly earlier in women (median age 25 years) than men (35.5 years). In 81% of women and 29% of men an environmental risk factor was present before first VTE. Oral contraceptives increased the risk of thrombosis 4-fold [odds ratio (OR) 4.0, 95% confidence interval (CI) 1.7, 10.4] in women with homozygous FV:G1691A. Postoperative and post-traumatic VTE as first manifestation occurred in 13% and 15% of surgical/traumatic events in patients and in 0.7% and 1.8% in reference group A, respectively (OR 19.7, 95% CI 2.5, 154 and OR 9.2, 95% CI 1.1, 79.4). Heterozygous FII:G20210A was more prevalent in symptomatic patients (11.7%) compared with reference group B (2.8%, OR 4.6, 95% CI 1.6, 13.2). The prevalence of homozygous MTHFR:C677T genotype was similar in patients and reference group B. Conclusions:,Our study supports the concept of thrombophilia as a multifactorial disorder. The knowledge of coexisting factors predisposing to VTE is useful for medical advice for primary and secondary prophylaxis in these patients. [source] Should children at risk for familial adenomatous polyposis be screened for hepatoblastoma and children with apparently sporadic hepatoblastoma be screened for APC germline mutations?,PEDIATRIC BLOOD & CANCER, Issue 6 2006Stefan Aretz MD Abstract Background Hepatoblastoma (HB) is the most frequent liver tumor in childhood, occurring in the first few years of life. Surgery combined with chemotherapy has resulted in dramatic improvements in prognosis. However, even today, about one quarter of affected children do not survive the disease. Compared to the general population, the risk of HB is 750,7,500 times higher in children predisposed to familial adenomatous polyposis (FAP), an autosomal-dominant cancer predispostion syndrome caused by germline mutations in the tumor suppressor gene APC. Only limited data exist about the frequency of APC germline mutations in cases of apparently sporadic HB without a family history of FAP. Procedure In our sample of 1,166 German FAP families, all known cases of HB were registered. In addition, 50 patients with apparently sporadic HB were examined for APC germline mutations. Results In the FAP families, seven unrelated cases of HB are documented; three had been detected at an advanced stage. In patients with apparently sporadic HB, germline mutations in the APC gene were identified in 10%. Conclusions These data raise the issue of the appropriate screening for HB in children of FAP patients. To date, the efficiency of surveillance for HB is unclear. In Beckwith,Wiedemann syndrome (BWS), recent studies suggest an earlier detection of both Wilms tumor and HB by frequent screening. We discuss the rationale and implications of a screening program; besides the examination procedure itself, screening for HB in children of FAP patients would have important consequences for the policy of predictive testing in FAP. In a substantial fraction of sporadic HB, the disease is obviously the first manifestation of a de novo FAP. These patients should be identified by routine APC mutation screening and undergo colorectal surveillance thereafter. Pediatric Blood Cancer 2006;47:811,818. © 2005 Wiley-Liss, Inc. [source] Mania as the first manifestation of Wilson's diseaseBIPOLAR DISORDERS, Issue 3 2008Alexandre Costa Machado Background:, Although mental changes are frequent in Wilson's disease, severe psychiatric disorders occur uncommonly and usually accompany the neurological picture. There are few reports in the literature of Wilson's disease patients with typical bipolar affective disorder (BPAD). Case report:, The authors report the case of a patient with Wilson's disease whose initial manifestation was a manic episode followed by depression. Tremor in the upper limbs appeared one year after the onset of symptoms. The diagnosis of Wilson's disease was established three years after the first symptoms appeared, based on the neuropsychiatric picture, the detection of Kayser,Fleischer rings and the results of diagnostic tests indicating chronic liver disease and copper excess. ATP7B genotyping and magnetic resonance imaging of the brain with proton spectroscopy study were also performed. The patient became asymptomatic two years after starting treatment with penicillamine and remained non-symptomatic controlled during the eight-year follow-up period, without any specific treatment for the BPAD. Conclusions:, To our knowledge, this is a singular report of a case of Wilson's disease in which a manic episode preceded the onset of neurological symptoms. The association between Wilson's disease and bipolar disorder is discussed. [source] Global Expression Profiling in Epileptogenesis: Does It Add to the Confusion?BRAIN PATHOLOGY, Issue 1 2010Yi Yuen Wang MBBS Abstract Since the inception of global gene expression profiling platforms in the mid-1990s, there has been a significant increase in publications of differentially expressed genes in the process of epileptogenesis. In particular for mesial temporal lobe epilepsy, the presence of a latency period between the first manifestation of seizures to chronic epilepsy provides the opportunity for therapeutic interventions at the molecular biology level. Using global expression profiling techniques, approximately 2000 genes have been published demonstrating differential expression in mesial temporal epilepsy. The majority of these changes, however, are specific to laboratory or experimental conditions with only 53 genes demonstrating changes in more than two publications. To this end, we review the current status of gene expression profiling in epileptogenesis and suggest standard guidelines to be followed for greater accuracy and reproducibility of results. [source] Epidemiology and clinical pattern of psoriatic arthritis in Germany: a prospective interdisciplinary epidemiological study of 1511 patients with plaque-type psoriasisBRITISH JOURNAL OF DERMATOLOGY, Issue 5 2009K. Reich Summary Background, Because psoriatic arthritis (PsA) usually develops years after the first manifestation of skin symptoms, in many cases the initial diagnosis of PsA depends on the dermatologist. Objectives, To investigate the prevalence and clinical pattern of PsA in a daily practice population of patients with psoriasis. Methods, Patients were enrolled in an observational prospective cross-sectional cohort study at 48 community and academic centres. Demographic and medical parameters were recorded, including severity of skin symptoms (Psoriasis Area and Severity Index, PASI), previous and current treatments, concomitant diseases, and the impact of psoriasis on productivity and health-related quality of life (Dermatology Life Quality Index, DLQI). Patients with joint symptoms were referred to a rheumatologist for diagnosis and to record the activity and pattern of arthritis. Results, Among 1511 patients 20·6% had PsA; in 85% of the cases PsA was newly diagnosed. Of these patients more than 95% had active arthritis and 53·0% had five or more joints affected. Polyarthritis (58·7%) was the most common manifestation pattern, followed by oligoarthritis (31·6%) and arthritis mutilans (4·9%). Distal interphalangeal involvement was present in 41·0% and dactylitis in 23·7% of the patients. Compared with patients without arthritis, patients with PsA had more severe skin symptoms (mean PASI 14·3 vs. 11·5), a lower quality of life (mean DLQI 11·6 vs. 7·7) and greater impairment of productivity parameters. Conclusions, The findings are consistent with a high prevalence of undiagnosed cases of active PsA among patients with psoriasis seen by dermatologists. As many of these patients also have significant skin symptoms, treatment strategies are required that are equally effective in the control of skin and joint symptoms of psoriasis. [source] Peripheral neuropathy as the first manifestation of Madelung's diseaseBRITISH JOURNAL OF DERMATOLOGY, Issue 3 2000E. Saiz Hervás No abstract is available for this article. [source] Cutaneous presentation of recurrence of lymphoepithelioid T-cell lymphoma (Lennert's lymphoma)CLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 2 2005C. Massone Summary Lennert's lymphoma (LL) is a T-cell lymphoma characterized by the presence of atypical T lymphocytes, admixed with histiocytes and epithelioid granulomas. Patients present with superficial lymph node involvement, mainly in the cervical areas; thoracic adenopathies and involvement of deep abdominal lymph nodes are rare. Cutaneous involvement is infrequent, reported to occur in only 4,11% of patients, and even rarer is the onset of cutaneous lesions as first sign of a recurrence. We report a female patient who presented with papules and nodules on the trunk and upper limbs as the first manifestation of recurrent LL. [source] Implantable cardioverter defibrillators for prevention of sudden cardiac DeathCLINICAL CARDIOLOGY, Issue 1 2007Rishi Sukhija M.D. Abstract Despite the multiple advances in the field of cardiovascular medicine, the incidence of sudden cardiac death (SCD) continues to rise. Of all SCDs, <25% occur in individuals deemed at high risk by current risk-stratification algorithms; hence, these risk-stratification algorithms are not satisfactory. Until better markers are identified to risk stratify patients, we will see an increasing use of implantable cardioverter defibrillators (ICDs). However, even with the increase in defibrillator use, the impact on overall incidence of SCD may only be modest, as many individuals experience SCD as the first manifestation of cardiovascular disease. Another important challenge is widespread availability of automated external defibrillators and effective utilization of public access defibrillation programs for timely and appropriate management of out-of-hospital victims with cardiac arrest. This review discusses the current understanding on SCD, risk stratification, and management aimed at reducing SCD, particularly with the use of ICDs. Copyright © 2007 John Wiley & Sons, Ltd. [source] Bone mineral density in hyperthyroidismCLINICAL ENDOCRINOLOGY, Issue 4 2004Helen Karga Summary objective, To investigate whether previous hyperthyroidism is a cause of permanent secondary osteoporosis. design and patients, In this cross-sectional study, 164 women with untreated or previously treated overt and symptomatic hyperthyroidism were examined 0,31 years after the initial episode of hyperthyroidism and its treatment, and were compared with a control group of 79 age-matched women without previous history of hyperthyroidism. Subjects with current or previous metabolic bone disease, any antiresorptive treatment for osteoporosis or treatments and habits known to affect bone metabolism were excluded. measurements, The age of the first manifestation of the disease, the age at the measurement of bone mineral density (BMD) at the spine and femoral neck and the interval between diagnosis and treatment of hyperthyroidism and BMD measurement were recorded and the Z-scores and T-scores of BMD were analysed. results, Untreated hyperthyroidism and hyperthyroidism up to 3 years after its diagnosis and treatment were associated with decreased BMD. Three or more years after the first episode of the disease the mean Z-score at both skeletal sites was near zero and not different from the controls. The age at which hyperthyroidism was manifested for the first time had no effect on the final outcome. Women affected at a young age (13,30 years) had a more pronounced loss of BMD when examined untreated or early (< 3 years) after diagnosis, but a BMD significantly above zero if examined later (> 3 years). Older women (aged 51,70 years) showed a similar pattern, although the differences were not significant. Middle-aged subjects (31,50 years) had the smallest loss of BMD during the first 3 years. Analysis of T-scores of former hyperthyroid women aged , 51 years showed no significantly different relative risk (RR) for osteoporosis in comparison with the controls. However, the study was not powered enough to give meaningful RR results. conclusions, Overt symptomatic hyperthyroidism is associated with decreased BMD during the first 3 years after diagnosis and treatment of the disease. After this interval, former hyperthyroid women have a Z-score near zero and not different from women without a history of the disease, apparently because of recovery of the bone density lost early during the course of the disease. Symptomatic hyperthyroidism does not seem to be a cause of long-lasting osteoporosis, and the age of the patient during the first episode is irrelevant. [source] No evidence found that childhood onset of psoriasis influences disease severity, future body mass index or type of treatments usedJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 11 2010MEA De Jager Abstract Background, In more than one-third of the psoriatic population, the first manifestations occur in childhood. Whether the age of onset of psoriasis influences the march of psoriasis is not known. Objectives, To describe the epidemiology and clinical features as well as prescribed treatments and familial distribution in psoriasis depending on the age of onset of the disease. Methods, A structured questionnaire was sent to 5300 adult psoriatic patients. Respondents were divided into two groups: patients who experienced an onset of disease before the age of 18 [childhood onset psoriasis (COP)] and patients with an onset of disease from the age of 18 [adult onset psoriasis (AOP)]. Results, Questionnaires of 1926 (36.3%) patients were suitable for analysis. In 37.1% of patients, first signs of the disease occurred before the age of 18. COP occurs predominantly in females, has a longer delay in diagnosis and a higher frequency of familial distribution. The development of guttate and erythrodermic psoriasis in adulthood is more frequently seen in COP. In contrast to common belief, type of psoriasis in COP often remains the same from childhood to adulthood. There was no evidence found that getting psoriasis before the age of 18 years influences development of high body mass index in adulthood, disease severity in later life or type of treatments used. Conclusions, The age of onset of psoriasis essentially does not influence the subsequent course of the disease in adulthood. [source] Cutaneous T-cell lymphomaJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 2 2003EA Kotz ABSTRACT Cutaneous T-cell lymphoma (CTCL) is a neoplasm of helper T cells whose first manifestations usually appear in the skin. The various forms of CTCL are distinguished by both clinical features and histopathology. Early on, the diagnosis may be difficult to establish because of its numerous, and often non-specific, clinical presentations. Further, the pathological findings of early lesions may lack the diagnostic features observed in well-developed or advanced disease. The diagnosis of CTCL must be considered in any patient with a chronic, therapy-resistant condition of the skin. In patients with non-specific histological findings, a high index of suspicion and multiple biopsies may eventually lead to a diagnosis of CTCL. Once the diagnosis of CTCL is established, accurate staging is essential both for its effect on treatment decisions and for its prognostic value. In general, CTCL is a chronic, slowly progressive disease with a long evolution. The development of tumours is a poor prognostic sign, as is erythroderma. The Sezary syndrome is a distinct form of erythrodermic CTCL that is characterized by exfoliative erythroderma, lymphadenopathy, lymphocytosis, intense pruritus, and circulating large, abnormal lymphocytes (Sezary cells). When death does occur, it is most often due to septicemia. Treatment of CTCL must be tailored to the individual patient. The most commonly employed treatment options are photochemotherapy and topical chemotherapy. [source] Epithelioid srcoma of the penis: A case report and review of the literaturePATHOLOGY INTERNATIONAL, Issue 7 2000Giulio Rossi A rare case of epithelioid sarcoma (ES) of the penis is presented. The patient, a 35-year-old man, was initially treated as having Peyronie's disease, but the subsequent appearance of a subcutaneous nodule displayed a ,distal-type' ES. At immunohistochemical phenotypification, the tumor was positive for vimentin, cytokeratins and epithelial membrane antigen (EMA), as well as for some other multidirectional antibodies, including a membranous reaction for CD99. The review of 11 similar cases so far reported in the literature led to the conclusion that the clinicopathological characteristics of penile ES are basically the same as those of tumors in more classical locations: the age at diagnosis ranged from 23 to 43 years, the interval between first manifestations and diagnosis averaged 37 months (delayed diagnosis being common because of the slow growth rate and the harmless appearance of the lesion), the typical sign was a superficial nodule or mass, usually accompanied (better preceded) by urethral stenosis, dysuria and erectile disturbances. Total or partial penectomy was the treatment of choice in most patients, but lack of adequate follow up did not permit any definitive conclusion to be reached regarding its efficacy. [source] | ||||||||||||||||||||||||||||