京都大学 / 新制・課程博士 / 博士(医学) / 甲第24317号 / 医博第4911号 / 新制||医||1062(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 小林 恭, 教授 溝脇 尚志, 教授 松田 道行 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Background and aims: The clinical course of prostate cancer is highly variable and difficult to predict.Stage at presentation, grade and PSA at diagnosis are traditionally used to predict outcome. The aimof this thesis was to identify strategies for improved survival prediction in men with prostate cancer.The way in which prostate cancer affects a population based‐cohort and how routinely measuredvariables can be used to predict survival in an intermediate to long follow‐up period were explored.From this large cohort we separately evaluated how survival can be predicted in men with incidentalcarcinoma (T1a and b) and locally advanced disease (lymph node‐ positive). Immunohistochemistrywas added to routinely measured variables in the subgroup of men with incidental carcinoma.Furthermore, we assessed how the outcome of metastatic disease may be predicted from informationavailable at diagnosis, and during the first six months after treatment. Finally we predicted survivalfor men with metastatic hormone‐refractory prostate cancer (HRPC). Material and methods: From the Swedish South‐East Region Prostate Cancer Register data on 8887men were studied and the impact of tumour grade, serum PSA concentration, TNM classification andtreatment was studied in relation to survival.Furthermore, an evaluation of the disease‐specific mortality of conservatively managed incidentalcarcinoma in relation to T‐category, Gleason score, p53, Ki‐67, Chromogranin A and serotonin wasmade. From the same register we studied whether common predictive factors such as serum‐PSA, Tcategoryand biopsy tumour grade could be used to better assess the prognosis of men with nodepositiveprostate cancer. Using data from the clinical trial SPCG‐5 we studied the possibility of serialmeasurements of PSA and ALP being to predict survival early in the course of hormone‐treatedmetastatic prostate cancer. From the same trial, we also assessed the value of PSA kinetics inpredicting survival and related this to baseline variables in men with metastatic HRPC. Results: In the South–East Region, where screening was seldom done the median age at diagnosisand death was 75 and 80 years respectively, and 12% were diagnosed before the age of 65 years. Hightumour grade, high serum PSA and high T category were associated with poor outcome. The projected 15‐year disease‐specific survival rate was 44% for the whole population. In total, 18% ofpatients had metastases at diagnosis and their median survival was 2.5 years. In the cohort of men with incidental carcinoma, 17% died of prostate cancer. Of 86 patients withGleason score ≤5, three died of prostate cancer. Independent predictors of disease‐specific mortality inmultivariate analysis were category T1b prostate cancer, Gleason score >5 and high immunoreactivityof Ki‐67. Men with lymph‐node positive disease have a median cancer‐specific survival of 8 years.Preoperatively known factors such as PSA, T‐category, age, mode of treatment, failed to predictoutcome, but there was a weak, not statistically significant difference in cancer‐specific survival inrelation to tumour grade. Initial ALP, and ALP and PSA after 6 months of treatment were the serum markers that provided thebest prognostic information about the long‐term outcome of metastatic prostate cancer. In men withHRPC, PSA velocity alone gave a better prediction of survival than all other PSA kinetic variables. Conclusion: In an almost unscreened population, prostate cancer is the elderly mans disease but themortality is high. Ki‐67 may be of value in addition to stage and Gleason score for predicting theprognosis in men with incidental carcinoma.The impact of lymph node metastases on survival overrides all other commonly used prognosticfactors. By following ALP and PSA for 6 months it is possible to predict outcome in metastatic prostate cancer.This gives a much better prediction than baseline PSA and helps to select men with a poor prognosis.By combining PSAV with the variables available at baseline, a better ground for treatment decisionmakingin men with HRPC is achieved.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19624号 / 医博第4131号 / 新制||医||1015(附属図書館) / 32660 / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 今中 雄一, 教授 佐藤 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Auf der Basis der Obduktionsprotokolle der Jahre 2000-2009 des Institutes für Pathologie des Universitätsklinikums Leipzig wurden die Häufigkeiten und Verteilungen maligner Tumoren sowie der zu Lebzeiten nicht bekannten malignen Tumoren untersucht. Bei insgesamt 4592 durchgeführten Sektionen wurden in 263 Fällen zu Lebzeiten nicht bekannte maligne Tumoren diagnostiziert. Dies entsprach 5,7% des gesamten Sektionsgutes bzw. 20,2% aller nachgewiesenen Malignome. Nach Analyse der pTNM-Klassifikation wurden 70,9% der Malignome in den Tumorkategorien pT1 und pT2 erfasst. In 24,7% der Fälle traten Lymphknotenmetastasen, in 19,4% Fernmetastasen auf. 23,2% der postmortal entdeckten Malignome waren todesursächlich. Über die Hälfte der Obduzierten mit klinisch nicht bekannten Tumoren waren 70 Jahre oder älter. Die häufigsten klinisch nicht bekannten malignen Tumoren waren die Prostatakarzinome (23,9%), die kolorektalen Karzinome (16,3%), die Nierentumoren (13,0%), die Lungenkarzinome (12,7%) sowie die Leberkarzinome (6,5%). Patienten mit synchronen Doppel- beziehungsweise Dreifachtumoren traten bei 1,8% des Sektionsgutes auf. Der Anteil nicht erkannter maligner Tumoren an den Mehrfachmalignomen betrug 41,7%. Diese Sektionsanalyse bestätigte, dass auch im 21. Jahrhundert trotz der rasanten Entwicklungen in Medizin und Technik weiterhin maligne Tumoren erst bei der Autopsie festgestellt werden.

Objectives: In our study, we evaluated and compared the prognostic value and performance of the 6th, 7th, and 8th editions of the American Joint Committee on Cancer (AJCC) staging system in patients undergoing surgery for perihilar cholangiocarcinoma (PHC). Methods: Patients undergoing liver surgery with curative intention for PHC between 2002 and 2019 were identified from a prospective database. Histopathological parameters and stage of the PHC were assessed according to the 6th, 7th, and 8th editions of the tumor node metastasis (TNM) classification. The prognostic accuracy between staging systems was compared using the area under the receiver operating characteristic curve (AUC) model. Results: Data for a total of 95 patients undergoing liver resection for PHC were analyzed. The median overall survival time was 21 months (95% CI 8.1–33.9), and the three- and five-year survival rates were 46.1% and 36.2%, respectively. Staging according to the 8th edition vs. the 7th edition resulted in the reclassification of 25 patients (26.3%). The log-rank p-values for the 7th and 8th editions were highly statistically significant (p ≤ 0.01) compared to the 6th edition (p = 0.035). The AJCC 8th edition staging system showed a trend to better discrimination, with an AUC of 0.69 (95% CI: 0.52–0.84) compared to 0.61 (95% CI: 0.51–0.73) for the 7th edition. Multivariate survival analysis revealed male gender, age >65 years, positive resection margins, presence of distant metastases, poorly tumor differentiation, and lymph node involvement, such as no caudate lobe resection, as independent predictors of poor survival (p < 0.05). Conclusions: In the current study, the newly released 8th edition of AJCC staging system showed no significant benefit compared to the previous 7th edition in predicting the prognosis of patients undergoing liver resection for perihilar cholangiocarcinoma. Further research may help to improve the prognostic value of the AJCC staging system for PHC—for instance, by identifying new prognostic markers or staging criteria, which may improve that individual patient’s outcome.

Background: Renal cell carcinoma (RCC) is most lethal of the urological cancers, with more than 40% dying of the disease. About 30% of the patients have metastases at initial diagnosis and up to 40% undergoing nephrectomy for localized RCC develop metastasis. A follow-up protocol based on accurate prognostic variables allows identification of low and high risk patients and selection of those most likely to benefit from adjuvant therapy. I have studied a number of prognostic patient-related factors, including tumour stage and grade, angiogenetic factors and tumour markers, in order to improve follow-up guideline as well as to try to predict prognosis and clinical outcome for individual patients. Material and Methods: The studies are based on patients treated for RCC between 1982 and 2002. All patients eligible for surgery with or without metastasis were treated with nephrectomy and were followed according to a scheduled follow-up programme. Serum samples were collected after obtained informed consent. Multiple clinicopathological, laboratory variables and preoperative radiological examinations were analyzed. Results: Study I- After nephrectomy in 187 patients with non-metastatic RCC, 30% developed metastases during the follow-up. The risk for metastases was greater for more advanced stage and was adjusted by size and DNA ploidy. The median time to the diagnosis of metastases was 14.5 months. Metastases occurred in 43% of the patients within one year, within 2 years in 70% and 80% in 3 years. Patients with tumours less than 5 cm and diploid pT1&gt;5cm and pT2 tumours survived longer than those with larger and aneuploid tumours. The 5-years survival rate for pT1, pT2, pT3 tumours were 95%, 87%, and 37% respectively. In pT3 tumours DNA ploidy had no relation to survival time. Study II and IV- The median survival time for patients with metastatic RCC was 7 months. Cytoreductive nephrectomy was associated with longer survival time. Factors including performance status (PS), number of metastatic sites, erythrocyte sedimentation rate (ESR), calcium in serum, vein invasion, capsule invasion had independent prognostic value with Cox multivariate analysis. Study III- The incidence of adrenal tumour involvement was 5.3 %, unaffected of RCC type, tumour location or side. Gender (male) and locally advanced tumours (pT3 &gt; 5cm) were factors predicting adrenal involvement. The presence of adrenal involvement was a significant adverse prognostic variable, indicating a significantly shorter survival in patients both with and without distant metastases. Conclusion: Optimal follow-up guidelines are important from both medical and economic perspectives. The risk for progression depends mainly on stage, which in combination with other prognostic factors may allow more individualized and cost effective follow-up, in some cases by avoiding unnecessary examinations in a third of the patients. Cytoreductive nephrectomy in patients with good PS, metastases limited to one organ, low ESR, normal calcium and no vein invasion were factors associated to long survival time. Soluble angiogenic factors in serum gave no prognostic information. Ipsilateral adrenalectomy in conjunction with radical nephrectomy should be performed if an adrenal lesion cannot be cleared of suspicion during preoperative work up. Ipsilateral adrenal involvement is a highly adverse prognostic factor and should be staged as M1a in the TNM staging system.

Auf der Basis der Obduktionsprotokolle der Jahre 2000-2009 des Institutes für Pathologie des Universitätsklinikums Leipzig wurden die Häufigkeiten und Verteilungen maligner Tumoren sowie der zu Lebzeiten nicht bekannten malignen Tumoren untersucht. Bei insgesamt 4592 durchgeführten Sektionen wurden in 263 Fällen zu Lebzeiten nicht bekannte maligne Tumoren diagnostiziert. Dies entsprach 5,7% des gesamten Sektionsgutes bzw. 20,2% aller nachgewiesenen Malignome. Nach Analyse der pTNM-Klassifikation wurden 70,9% der Malignome in den Tumorkategorien pT1 und pT2 erfasst. In 24,7% der Fälle traten Lymphknotenmetastasen, in 19,4% Fernmetastasen auf. 23,2% der postmortal entdeckten Malignome waren todesursächlich. Über die Hälfte der Obduzierten mit klinisch nicht bekannten Tumoren waren 70 Jahre oder älter. Die häufigsten klinisch nicht bekannten malignen Tumoren waren die Prostatakarzinome (23,9%), die kolorektalen Karzinome (16,3%), die Nierentumoren (13,0%), die Lungenkarzinome (12,7%) sowie die Leberkarzinome (6,5%). Patienten mit synchronen Doppel- beziehungsweise Dreifachtumoren traten bei 1,8% des Sektionsgutes auf. Der Anteil nicht erkannter maligner Tumoren an den Mehrfachmalignomen betrug 41,7%. Diese Sektionsanalyse bestätigte, dass auch im 21. Jahrhundert trotz der rasanten Entwicklungen in Medizin und Technik weiterhin maligne Tumoren erst bei der Autopsie festgestellt werden.