Rationale/Objective: Excess lung cancer risks associated with exposure to inhaled radon decay products among uranium miners has well been established. Although ingestion is also a potentially important route of exposure, the relationship between ingested radon decay products and gastrointestinal cancer risks are not well examined. The objective of this study is to determine the relationship between exposure to radon decay products and the incidence and mortality of gastrointestinal (esophagus, stomach, and colorectal) cancer among men employed as uranium miners in Ontario. Secondly, to determine whether the duration of exposure (dose rate), years since last exposure and age at first exposure modify these associations. Methods: A cohort of miners who had ever worked in an Ontario uranium mine between 1954 and 1996 was created using the Mining Master File and the National Dose Registry. Cumulative radon exposures measured in Working Level Months (WLM) were previously estimated for each miner. Cancer diagnoses (1964-2004) and cancer deaths (1954-2004) occurring in Ontario were determined by probabilistic record linkage with the Ontario Cancer Registry. To calculate person-years at risk, non-cancer deaths were also ascertained from the Ontario mortality file for the period between 1954 and 2004. Poisson regression methods for grouped data were used to estimate the relative risks (RR) and 95% Confidence Intervals (CI) by exposure level. Results/Conclusions: The final cohort consisted of 28,273 Ontario uranium miners. By the end of 2004, 34 miners had been diagnosed with esophageal cancer, 86 with stomach cancer, and 359 with colorectal cancer. There were 40 deaths due to esophageal cancer, 69 from stomach cancer, and 176 from colorectal cancer. When comparing the highest cumulative exposure category (>40 WLM) to the referent group (0 WLM), significant increases in both stomach (RRIncidence= 2.30, 95% CI;1.02-5.17 and RRMortality=2.90, 95% CI;1.11-7.63) and colorectal cancers (RRIncidence =1.56, 95% CI;1.07-2.27 and RRMortality =1.74, 95% CI;1.01-2.99) after adjusting for age at risk and period effects. However, no relationships were observed for esophageal cancer. Suggestive evidence of modifying effects of these associations by duration of employment (dose rate) and years since last exposure for colorectal cancer was also observed.

The esophageal squamous cell carcinoma (ESCC) is known to be one of the most difficult malignancies to treat among digestive carcinomas. The esophageal squamous cell carcinoma and adenocarcinoma are the two most common cell types of esophageal cancer in the world. Even though the incidence of esophageal adenocarcinoma has been dramatically increasing in Western populations during the past two decades, esophageal squamous cell carcinoma remains the predominant type of esophageal malignancy in the remainder of the world. In Taiwan, ESCC is the ninth leading cause of cancer deaths, the 6th among male. In spite of advances in surgical techniques and perioperative management in recent decades, current modalities of therapy for this disease still offer poor survival and cure rates. Even in resectable diseases, the 5-year survival rates were only less than 20%. Recently, esophageal squamous cell carcinoma and adenocarcinoma were increasingly recognized as two entities with different biologic behavior and outcome. Consequently, the surgical risks and oncologic benefits of esophagectomies for esophageal squamous cell carcinoma patients are controversial and not confessed. From 1991 to 2003, 216 esophageal squamous cell carcinoma patients underwent esophagectomy were enrolled and analyzed retrospectively. Among these patients, 166 patients underwent transthoracic esophagectomy and 50 patients underwent transhiatal esophagectomy. The overall hospital mortality and postoperative complication rates were 9.7% and 49%, respectively. The overall 5-year survival rate was 16.8%. The hospital mortality rate, postoperative complication rate, length of hospital stay and amount of intra-operative blood loss or transfusion were not significantly different between both groups. But, shorter operative time was noticed in transhiatal group (p<0.001). Patients underwent either transthoracic or transhiatal esophagectomy had comparable long-term survival. The pTNM stage was independent prognostic factors for patients underwent transthoracic esophagectomy. However, location of tumors (p=0.0085) and pathologic tumor length (p=0.0118) were significant predictors for patients underwent transhiatal esophagectomy. In this part of study, we found that both transthoracic and transhiatal esophagectomies could provide comparable survival benefits for esophageal squamous cell carcinoma patients. However, the traditional pTNM staging system might underestimate the severities of ESCC patients who underwent transhiatal esophagectomy. Due to the dismal results of ESCC patients after surgery and the findings of multi-environmental and/or genetic factors involved in the carcriogenesis of ESCC, further realizing the molecular mechanisms of carcinogens in the development of esophageal squamous cell carcinoma is crucial for prevention and treatment for this disease. Epidemiological analysis showed that the prevalence of esophageal squamous cell carcinoma varied in different geographic areas. The various prevalence of disease in different parts of the world reflects different forms and extents of exposure to these etiological agents involving the development of this disease. In stead of tobacco and alcohol, recent reports indicated that betel quid (BQ) chewing also significantly correlated with the occurrence of esophageal squamous cell carcinoma in Taiwanese. The mechanisms behind the BQ-related esophageal squamous cell carcinoma in Taiwan are worthy for further investigation. Previous studies have shown that certain carcinogens may induce a ¡§fingerprint-like¡¨ ¡V like pattern of mutations at the p53 gene, both in terms of mutation type and codon specificity. However, the role of p53 mutation in the etiology of esophageal squamous cell carcinoma has not been rigorously studied in Taiwan. The incidence of p53 mutations in ESCC associated with risk factors has not been explored in Taiwanese. Accordingly, 75 primary esophageal squamous cell carcinoma specimens were collected for examining the incidence of mutations in the conserved regions of p53 gene by using polymerase chain amplification and direct sequencing of amplified products. There were 37 mutations of p53 gene detected in 45.5% (34/75) of tumor specimens. These mutations significantly clustered in exon 5 (21/37) of p53 gene. The incidence of p53 mutations didn¡¦t associate with clinicopathological characteristics and habits of cigarette smoking or alcohol drinking. However, BQ chewer exhibited significantly higher incidence of p53 gene mutations than non-chewer (67.6% vs. 32.4%, p=0.007). After controlling confounding factors of cigarette smoking and alcohol drinking, BQ chewing still showed significant impact on the incidence of p53 mutation in esophageal squamous cell carcinomas (RR=4.233; 95% CI, 1.317-13.603). The A:T to G:C transition (8/37, 21.6%) and G:C to T:A transversion (5/23, 13.5%) were the prevalent spectrum of p53 gene mutations. All A:T to G:C transitional mutations occurred in patients with habits of betel quid chewing and cigarette smoking. Noticeably, alcohol drinking could enhance this peculiar spectrum of p53 mutation in esophageal squamous cell carcinoma. Therefore, p53 gene might be one of the molecular targets of betel quid carcinogens in the development of esophageal squamous cell carcinoma in Taiwanese. Determination of the importance of p53 gene mutation in ESCC requires further study. To elucidate the role of cell cycle associated genes in ESCC, 40 primary esophageal squamous cell carcinoma patients were included in this part of study. Tissue samples were analyzed for cell proliferation, DNA content, mutation of p53 gene, and expression of p16, p21waf1/cip1, pRb and p53 proteins. In this part of study, 75% of tumors exhibited aneuploid DNA content. Significantly higher S-phase fractions were detected in tumor samples (p<0.001). The p53 immunostaining was detected in 62.5% (25/40) of tumor tissues and 50% of tumors were p21waf1/cip1 overexpression. The p16 protein was only detected only in 8 of the 40 ESCC (20.0%) tissue samples by immunohistochemistry. The nucleus stained Rb protein was detected in 38 ESCC tissue samples and all of them were phosporylated status. The phosphorylation of pRb at Ser-795, Ser-789 and Ser-807/811 was detected in 87.5% (35/40), 72.5 (29/40) and 42.5% (17/40) of ESCC tissue samples, respectively. Expression of p16 protein, total pRb or phospho-Rb expression status did not correlate with the clinicopathological parameters of patients. The overexpression of p21waf1/cip1 protein didn¡¦t correlate with p53 gene status, but significantly correlated with the existence of abnormal DNA content (P=0.028). Advanced pTNM stage, lymph node metastasis and p21waf1/cip1 overexpression conferred survival disadvantages in univariate analysis (P=0.013, 0.045 and 0.017, respectively). A Cox multivariable analysis revealed pTNM stage (IIB/III/IV vs. I/IIA; p=0.024) associated with p21waf1/cip1 overexpression (positive vs. negative; p=0.035) as independent prognostic factors in esophageal squamous cell carcinomas. Surprisingly, p21waf1/cip1 overexpression significantly compromised the survival of patients with mutated p53 gene (p=0.035). However, no significant dismal effect of p21waf1/cip1 overexpression can be seen in patients with wild-type p53 gene (P=0.175). Consequently, overexpression of p21waf1/cip1 is correlated with chromosomal instability and serves as an adverse prognostic predictor for esophageal squamous cell carcinoma patient. Its dismal effect is more prominent when p53 gene is mutated. The ribonucleotide reductase (RNR) is an S phase-specific dimeric enzyme and is the rate-limiting enzyme of DNA synthesis pathway responsible for the reduction of all four ribonucleotides to their corresponding deoxyribonucleotides (dNTPs), which are the building blocks for DNA replication and repair in all living cells. The RNR enzyme was formed by the association of RRM1 and RRM2 subunits. Normally, the levels of RRM2 expression modulate the RNR enzymatic activity. However, RRM2 also plays an important role in other aspects of the malignant phenotype such as tumor development and drug resistance. Recently, the p53-inducible ribonucleotide reductase small subunit homologue, p53R2, has been isolated and shown to play a crucial role in DNA repair after DNA damage. However, the function of p53R2 is still unclear especially in tumor cells. By immunohistochemistry, the expression of RRM2 and p53R2 proteins were detected in 94.1% (80/85) and 55.3% (47/85) of ESCCs tissue samples, respectively. No significant correlation could be found between RRM2 protein expression and gender, depth of tumor invasion, lymph-node involvement and pTNM stage. The p53R2 expression status also did not correlate with the gender of patients and the depth of tumor invasion. However, the presence of p53R2 protein expression significantly correlated with pTNM stages of tumors (p=0.027) and lymph node metastasis (p=0.009). In Cox multivariable regression analysis, p53R2 expression (positive vs. negative; p=0.011, HR: 3.096, 95% CI: 1.294-7.407) together with pTNM stage (IIB/III/IV vs. I/IIA; p=0.005, HR: 2.496, 95% CI: 1.320-4.719) was shown to have independent prognostic impact on survival of ESCC patients. Accordingly, in the analysis of cell cycle associate genes, the p53 mutations associated with loss of Rb pathway function would be the critical event in the development of human esophageal squamous cell carcinoma. In ESCC, loss of p53 pathway function is attributable to p53 mutations. However, the Rb pathway might be perturbed by inactivation of p16 and over-expressed p21waf1/cip1 protein in ESCC tissues. Consequently, the perturbed Rb function results in up-regulation ribonucleotide reductase activity, causing DNA precursors overproduction and cell proliferation. Using immunohistochemistry, our findings provide the first evidence of RRM2 and p53R2 expression in human ESCCs. We identified the different prognostic effects of RRM2 and p53R2 expression in human ESCCs. The identification of different roles of p53R2 and RRM2 involved in the carcinogenesis of esophageal squamous cell carcinomas might be useful for designing more effective RRM2 or p53R2 specific target therapy for esophageal squamous cell carcinoma to improve the clinical outcome of patients with esophageal carcinoma.

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 117-143).

Κλινικά προσδιορισμένες σχέσεις Δόσης –Απόκρισης για τη στένωση του οισοφάγου από ακτινοθεραπεία κεφαλής και τραχήλου Σκοπός Ο σκοπός αυτής της μελέτης είναι ο προσδιορισμός των παραμέτρων δόσης απόκρισης του μοντέλου σχετικής σειριακότητας αναφορικά με το κλινικό αποτέλεσμα της στένωσης του οισοφάγου μετά από ακτινοθεραπεία κεφαλής και τραχήλου. Αυτό επιτυγχάνεται με τη συσχέτιση των ξεχωριστών τρισδιάστατων κατανομών δόσης των ασθενών με τα αντίστοιχα μετακτινικά αποτελέσματα από την κλινική παρακολούθηση. Υλικά και μέθοδοι Αυτή η μελέτη είναι βασισμένη σε 72 ασθενείς που υποβλήθηκαν σε ακτινοθεραπεία για καρκίνο κεφαλής και τραχήλου στο νοσοκομείο Καρολίνσκα της Στοκχόλμη Σουηδίας. Η ανάλυση έγινε για τις περιόδους 1991-2000 και 2001-2005, λόγω των διαφορετικών τεχνικών ακτινοβόλησης που χρησιμοποιήθηκαν. Για κάθε ασθενή υπολογίσθηκαν οι τρισδιάστατες κατανομές δόσης των ανώτερων 5εκ. του οισοφάγου και ήταν διαθέσιμα τα κλινικά αποτελέσματά της θεραπείας. Για να εκτιμηθεί η εμφάνισή της προκαλούμενης από ακτινοβολία στένωσης του οισοφάγου, χρησιμοποιήθηκαν κλινικά συμπτώματά και ακτινολογικά ευρήματα. H διάγνωση της στένωσης έγινε 1-60 μήνες μετά την ακτινοθεραπεία. 33 ασθενείς ανέπτυξαν στένωση του οισοφάγου ενώ 39 ασθενείς δεν εκδήλωσαν κανένα σύμπτωμα. Τα δεδομένα χρησιμοποιήθηκαν σε μια διαδικασία προσαρμογής μέγιστης πιθανοφάνειας (maximum likelihood fitting) ώστε να υπολογιστούν οι βέλτιστες τιμές των παράμετρων που χρησιμοποιούνται από το μοντέλο σχετικής σειριακότητας. Αποτελέσματα Για την περίοδο 1991-2000, η μέση και η μέγιστη τιμή της δόσης είναι 49.9 και 61.2Gy, αντίστοιχα για την ομάδα ασθενών με στένωση, ενώ για την ομάδα έλεγχου οι αντίστοιχες τιμές είναι 46.3 και 64.8Gy. Για την περίοδο 2001-2005 αυτές οι τιμές είναι 49.8 και 61.4Gy για την ομάδα ασθενών με στένωση, ενώ για την ομάδα έλεγχου είναι 20.6 και 46.1Gy, αντίστοιχα. Για την περίοδο 2001-2005 οι βέλτιστες εκτιμήσεις των παραμέτρων δόσης απόκρισης είναι D50=62.3 Gy (52.4-87.3 Gy), γ = 1.14 (0.74-2.28) και s = 0.11 (0.01-0.33). Επίσης, βρέθηκε στατιστικά σημαντική θετική συσχέτηση των στενώσεων που προκαλούνται από την ακτινοβολία με τη βιολογικά ομοιόμορφη δόση στα 50 Gy (odds ratio (OR) = 13.0 με 95% διάστημα εμπιστοσύνης (confidence interval, CI) = 2.9-58.6). Επιπλέον, το μοντέλο σχετικής σειριακότητας φαίνεται να διαφοροποιεί καλά τις ομάδες ασθενών με και χωρίς στένωση, καθώς σύμφωνα με την ανάλυση η περιοχή κάτω από της καμπύλη ROC είναι ίση με 0.92. Συμπεράσματα Βρέθηκε ότι οι στενώσεις που προκαλούνται από ακτινοβολία έχουν ισχυρή συσχέτηση με τον όγκο (χαμηλή σχετική σειριακότητα). Σημαντικά μεγαλύτερες μέσες και μέγιστες τιμές δόσεων χαρακτηρίζουν την ομάδα των ασθενών με στένωση σε σχέση με την ομάδα των ασθενών χωρίς στένωση. Οστοσο τα δεδομένα δείχνουν οτι ισως υπάρχουν και αλλες παράμετροι εκτώς απο τη δόση που συμβάλουν στην ανάπτυξη της στένωσης του οισοφάγου μέτα την ακτινοθεραπεία κεφαλής τραχήλου. / Dose-Response Parameters of Stricture in the Proximal Esophagus from Head & Neck Radiotherapy Purpose The purpose of this work is to determine the dose-response parameters of the relative seriality model regarding the clinical endpoint of esophageal stricture after head & neck radiotherapy. This is accomplished by associating the individual 3-dimensional dose distributions of the patients with the clinical follow-up findings. Material and Methods This study is based on 72 patients who received radiation treatment for head & neck cancer at Karolinska Hospital, Stockholm, Sweden. The analysis was conducted for the periods 1991-2000 and 2001-2005 because of the different irradiation techniques used. For each patient the 3D dose distribution delivered to the upper 5 cm of the esophagus (proximal esophagus) and the clinical treatment outcome were available. Clinical symptoms and radiological findings were used to assess the manifestation of radiation induced esophageal strictures. Stricture was diagnosed 1–60 months after radiotherapy. 33 patients developed esophageal stricture and 39 were symptom free. These data were introduced into a maximum likelihood fitting to calculate the best estimates of the parameters used by the relative seriality model. Results For the period 1991-2000, the mean and maximum doses are 49.9 and 61.2 Gy, respectively for the group of patients with stricture, whereas they are 46.3 and 64.8 Gy, respectively for the control group. For the period 2001-2005 these values are 49.8 and 61.4 Gy, respectively for the group of patients with stricture, whereas they are 20.6 and 46.1 Gy, respectively for the control group. For the period 2001-2005 the best estimates of the dose-response parameters are D50=62.3 Gy (52.4-87.3 Gy),  = 1.14 (0.74-2.28) and s = 0.11 (0.01-0.33). A statistically significant positive association of radiation induced esophageal stricture with the biologically effective uniform dose (cutoff at 50 Gy) was found (odds ratio (OR) = 13.0 with 95% confidence interval (CI) of 2.9-58.6). Furthermore, the relative seriality model seems to differentiate well the patient groups with and without stricture since in a ROC analysis it gives the area under the ROC curve = 0.92. Conclusions Radiation induced strictures were found to have a strong volume dependence (low relative seriality). Significantly larger mean and maximum doses characterize the group of patients with stricture compared to the group of patients without stricture. However, data indicate that there may be other factors, except from dose, that contribute to the development of oesophageal stricture after the radiation therapy.

Pressure within the esophagus arises from two mechanisms: intrabolus pressure, which is a hydrodynamic phenomenon, and esophageal occlusion pressure, which is a contact phenomenon. Current esophageal manometers are sensitive to both hydrodynamic and contact pressures and cannot distinguish between the two measurements in the absence of other information. It has been shown that measurement of intrabolus pressure is a clinically relevant parameter in esophageal manometry. There is no single device available that can obtain this measurement directly. This work presents a novel fibre optic-based flexible catheter for high resolution manometry with sensing pods that can be selectively sensitized to either hydrodynamic pressure alone, or contact and hydrodynamic pressure, offering sensing schemes not possible with existing high resolution manometers. The catheter is designed to be used with a time division multiplexing interrogation technique, yielding a system capable of exceeding the 36-sensor count limit of current solid state manometers. The device consists of rigid sensing pods connected by flexible tubing with in-fiber Bragg gratings acting as sensing elements within each of the pods. Absent in each sensing pod are rigid anchor points, representing a novel departure from comparable designs and resulting in increased sensitivity and decoupling from axial loading. Device functionality is demonstrated through bench top trials. A pressure sensitivity of 1.8 pm/mmHg and axial sensitivity of 11 mmHg/N of applied load is demonstrated. Crosstalk between individual sensors is characterized and a compensation scheme is developed and validated. Temperature response is demonstrated to be linear such that its confounding can be corrected for procedurally. Sensing schemes afforded by this design may yield clinically relevant parameters not achievable by any single existing device. / Graduate

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 49-56).