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- Kjellman, Petra
(författare)
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Clinical and molecuar studies of papillary thyroid carcinoma : with an emphasis on prognostic factors
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Thyroid cancer accounts for approximately 1% of all cancers reported. In Sweden 45/100, 000 inhabitants annually present with thyroid carcinoma. There are four different variants of thyroid carcinoma: papillary thyroid carcinoma (PTC), follicular thyroid carcinoma, medullary thyroid carcinoma and anaplastic thyroid carcinoma. PTC comprises 60-80% of thyroid cancers. The PTC prognosis is usually excellent with a long-term survival rate exceeding 90%. However, some patients develop distant metastases or die from the disease, and these are classified as having aggressive PTC. With the aim to predict the prognosis at the time for surgery, several prognostic factors have been established. Still, the natural course of the disease cannot always be predicted from the initial clinical presentation. Hence, there is a need for additional markers for the identification of patients who are at risk of developing aggressive PTC. To evaluate associations between clinical and histopathological features and the patients' outcome, 220 patients who underwent surgery for PTC at the Karolinska University Hospital, Solna between 1980 -1999 were reviewed retrospectively. Of these, 19 patients (9%) developed aggressive PTC. Due to invasive tumor growth radical surgery could not be performed in 58% of these patients as compared to in 2% of the patients with non-aggressive PTC. Non-radical surgery proved the most powerful predictor for development of aggressive PTC. The reported excellent prognosis for patients < 45 years of age could not be confirmed; three of the patients who eventually died from PTC were below the age of 45 (Paper I). The antibody MlIB-1 detects the Ki-67 antigen in proliferating cells. To investigate if assessment of the percentage of MIB-1 positive cells (MIB-1 index) can add prognostic information in PTC, MIB-1 immunoreactivity was analyzed in 30 PTCs. Thirteen patients were classified as having aggressive PTC, and tumors from these patients had a significantly higher MIB-1 index (median 5.4%) as compared to those from patients with non-aggressive PTC (median 1.1%). MIB-1 index >= 1.85% was found to be an independently significant risk factor for aggressive PTC (Paper II). The RET proto-oncogene encodes a receptor tyrosine kinase normally not expressed in thyroid follicular cells. RET can be activated through rearrangements, generating the fusion oncogene RET/PTC. Today several variants have been described, but their association to clinical outcome is debated. To search for expression of RET or the oncogenes RET/PTC1 -4, 61 PTCs were analyzed using RT-PCR. RET-TK expression was detected in 48%. This proved to be due to a RET/PTC rearrangement in three cases only, and expression of wild-type RET in 12 cases. The remaining 14 tumors expressed RET-TK only, indicating presence of yet unidentified rearrangements. Expression of wild-type RET was detected significantly more often in aggressive PTCs and in poorly differentiated PTCs (Paper III). In an attempt to identify chromosomal regions harboring potential oncogenes and tumor suppressor genes involved in PTC initiation and progression, 25 PTCs were screened for chromosomal imbalances using comparative genomic hybridization (CGH). Gain of 9q was the most common change, detected in close to 30% of the tumors. The total number of alterations was higher in tumors from patients with aggressive PTC. Gain of 1q and loss of 9q were exclusively seen in tumors from patients with aggressive disease, suggesting the location of genes important for PTC progression in these regions (Paper IV). In summary, complete removal of all tumor cells appears to be most important and postoperative I131 treatment probably cannot compensate for an incomplete tumor resection. MIB-1 index is a valuable prognostic marker, which can add prognostic information to established prognostic parameters. RET/PTC1-4 oncogenes are rare in Swedish tumors, suggesting other mechanisms involved in PTC development. Still, expression of RET-TK may be of prognostic importance, and may point towards new treatment modalities. Although PTC is generally a genetically stable tumor, aggressive PTC tumors exhibit signs of chromosomal instability. At least three chromosomal regions have been defined as potential locations for tumor suppressor genes or oncogenes involved in PTC. Gain of 9q may be an early event, while loss of 1q and 9q may be involved in progression toward aggressive variants of PTC.
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| 2. |
- Svedbom, Axel, et al.
(författare)
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Long-term Outcomes and Prognosis in New-Onset Psoriasis
- 2021
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Ingår i: JAMA dermatology. - : American Medical Association (AMA). - 2168-6068 .- 2168-6084. ; 157:6, s. 684-690
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Tidskriftsartikel (refereegranskat)abstract
- Importance Psoriasis is a heterogeneous disease. Improved understanding of prognosis and long-term outcomes in new-onset psoriasis may improve care.Objective To describe the clinical course of psoriasis and identify possible indicators of long-term outcomes.Design, Setting and Participants The Stockholm Psoriasis Cohort was a noninterventional inception cohort study enrolling patients between 2001 and 2005. The present study was conducted from January 15, 2019, to February 5, 2021. At enrollment and 10 years, patients were examined by dermatologists and rheumatologists. Data from examinations were complemented by questionnaires, medical records, and registers. A total of 721 patients with recent-onset psoriasis (<12 months duration), 15 years or older were recruited using advertising and referrals from a broad range of health care settings.Main Outcomes and Measures Disease severity and psoriatic arthritis (PsA). Recursive partitioning and regression models were implemented to identify probable indicators of long-term outcomes.Results A total of 721 patients (median [interquartile range] age, 39 [27-55] years; 405 [56%] women), including 542 (75%) with plaque-onset and 174 (24%) with guttate-onset psoriasis, were enrolled. The median follow-up was 9.6 years (interquartile range, 8.8-10.4 years). The cumulative incidence of severe psoriasis at 12 years from enrollment was 21%. Among 509 patients examined clinically after 10 years, 77 of 389 patients (20%) with plaque onset and 56 of 116 (48%) with guttate onset had minimal disease activity without treatment, and 120 of 509 (24%) had PsA. Recursive partitioning identified strata with distinct risks for severe skin disease and PsA: the cumulative incidence of severe disease in patients with plaque phenotype, above-median disease activity, and scalp lesions was 52% (95% CI, 41%-64%), compared with 11% (95% CI, 8%-14%) in patients with below-median disease activity at inclusion; and 48 of 82 patients (59%) with peripheral enthesitis had PsA after 10 years compared with 37 of 304 patients (12%) without initial joint pain (P < .001). Smoking (hazard ratio, 1.70; 95% CI, 1.10-2.63) and activating genes in the interleukin-23 (IL-23) pathway (odds ratio, 1.55; 95% CI, 1.14-2.11) were also significantly associated with a severe disease course. Systemic therapy at or before enrollment was associated with a lower risk for severe disease at 10 years compared with later initiation of systemic therapy (odds ratio, 0.24; 95% CI, 0.06-0.90).Conclusions and Relevance The findings of this cohort study suggest that combinations of clinical characteristics at onset and activating genes in the IL-23 pathway are significantly associated with the clinical course of psoriasis, whereas joint pain and peripheral enthesitis may indicate the probability of PsA. Patients within those categories merit specialist referral and closer follow-up. The possibility of modifying the disease course with early systemic intervention should be tested.
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