Germ cell tumors (GCT) are uncommon malignancies in adult males and comprise less than 1% of male cancers. Due to highly curative nature and productive life years gained after treatment; reduction of chemotherapy related toxicities becomes vital. Cisplatin is the backbone of GCT chemotherapy, & is related to myocardial injury, thromboembolism & vasculitis. Though it should not be replaced with Carboplatin, however in certain circumstances, its use maybe unsafe; especially in cases when patient have prior myocardial infarction. We report a case of Takotsubo cardiomyopathy (TCM)secondary to GCT diagnosis in a young male. This patient presented withsymptoms of myocardial infarction however, coronary angiography was normal and a diagnosis of TCM was made. Though, it is rare but a unique challenge, as whether Cisplatin use would be safe in this particular scenario? On one hand patient had stress related myocardial injurywhile he was also at risk of further Cisplatin induced complications.There are no clear cut guidelines, so after informed consent his treatment regimen was modified to EC (Etoposide/Carboplatin) instead of EP (Etoposide/Cisplatin). Patient has completed 4.6 years of follow-up without any evidence of relapse. We suggest informed decisions and to weigh the pros and cons of using an inferior regimen, in order to achieve same long term prognosis while preventing any acute complications,in younger patients with curable cancers.

The dose-response ototoxic effects of cisplatin were studied in guinea pigs. Loss of Preyer reflex and suppression of the N1 amplitude occurred in cisplatin-treated animals and was described as dose-related. Drug-induced hair cell damage, as observed with scanning electron microscopy, occurred sporadically throughout the turns of the cochlea and the incidence increased with dose. Na, K-ATPase activity in the lateral wall tissues was not significantly different between treatment groups. The results reported here indicate that cisplatin ototoxicity was dose-dependent, but was not directly related to Na,K-ATPase activity in the lateral wall.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24130号 / 医博第4870号 / 新制||医||1059(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 中島 貴子, 教授 万代 昌紀, 教授 武藤 学 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23565号 / 医博第4779号 / 新制||医||1054(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 武藤 学, 教授 万代 昌紀, 教授 上杉 志成 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Tumore von Kopf und Hals gehen weiterhin mit einer schlechten Prognose einher. Im Rahmen einer operativen Therapie tritt Wundsekret (WS) aus, welches der Wundheilung dient. Dieses kann in Kontakt mit Tumorzellen bzw. Resttumor in der Wunde kommen. Im Rahmen der vorliegenden Arbeit wurde die Frage nach dem Einfluss von Wundsekret auf Zellvermehrung, Chemoresistenzentwicklung, den Zellzyklus und die Induktion einer Epithelial-mesenchymalen Transition (EMT) in Tumorzellen von Kopf und Hals gestellt. Hierfür wurde das WS von Tag1 und das WS von Tag 2 im Dotblot auf seine Zytokinzusammensetzung analysiert. Zwei Tumorzelllinien von Kopf und Hals, FaDu und HlaC78, wurden mit WSTag1 und WSTag2 behandelt und untersucht, welche Effekte das WS auf die Zellen hat. Verwendet wurden ein Proliferationsassay, eine Zellzyklusuntersuchung und Apoptosetestung mittels FACS, eine PCR, ein Spheroidmodell und die Lichtmikroskopie. Im WS wurden erhöhte Konzentrationen verschiedener Zytokine, insbesondere von IL-6, nachgewiesen. Gezeigt werden konnte eine gesteigerte Proliferationsrate der Tumorzellen unter WS-Behandlung, jedoch keine veränderte Verteilung der Zellzyklusphasen. In HlaC78-Zellen konnte eine vermehrte Vitalität nach Cisplatinbehandlung nachgewiesen werden. In beiden Tumorzelllinien fand sich eine vermehrte Exprimierung von Snail 1, Snail 2 und Vimentin. E-Cadherin wurde vermindert exprimiert. Twist und N-Cadherin wiesen keine Veränderungen auf. Es zeigte sich eine vermehrte Migration der Tumorzellen in die Umgebung. Die Zellen wiesen nach Behandlung mit WS vermehrt mesenchymale Zeichen auf. Es konnte kein Unterschied der Auswirkungen einer Behandlung mit WSTag1 im Vergleich zu einer Behandlung mit WSTag2 festgestellt werden. Insgesamt scheint WS in Tumorzellen von Kopf und Hals einen EMT-artigen Prozess in Gang zu setzen, also eine partial EMT (pEMT). Als mögliche Auslöser dieser Veränderungen kommen die im WS nachgewiesenen Zytokine und v. a. IL-6 in Frage. / Tumors of the head and neck continue to be associated with a poor prognosis. In the course of surgical therapy, wound fluid (WF) may come into contact with tumor cells or residual tumor in the wound. In this study, the influence of wound fluid on cell proliferation, development of chemoresistance, the cell cycle and the induction of an epithelial-mesenchymal transition (EMT) in tumor cells of the head and neck was investigated. Therefore, WF from day 1 and WF from day 2 were analyzed for their cytokine composition by Dotblot. The effects of WF from day 1 and WF from day 2 on two tumor cell lines of the head and neck, FaDu and HlaC78, were investigated using a proliferation assay, a cell cycle assay and an apoptosis assay via FACS, PCR, a spheroid model and light microscopy. Increased concentrations of various cytokines, especially IL-6, were detected in the WF. An increased proliferation rate of tumor cells under WF treatment could be shown. There was no alteration in the distribution of cell cycle phases, however. In HlaC78 cells an increased vitality after cisplatin treatment could be proven. Increased expression of Snail 1, Snail 2, and Vimentin was found in both tumor cell lines. The expression of E-cadherin was decreased. Twist and N-cadherin showed no changes. Increased migration of tumor cells to the surrounding area could be seen. Cells showed more mesenchymal signs after treatment with WF. No difference in the effects of treatment with WF from day 1 compared to treatment with WF from day 2 was observed. Overall, WF appears to initiate an EMT-like process in tumor cells of the head and neck, this is called partial EMT (pEMT). Possible inducers of these changes are the cytokines and in particular IL-6 that have been found in WF.

INTRODUCTION: In patients who receive treatment for cancer, acute kidney injury (AKI) is arguably one of the most dangerous toxicities that results from cisplatin (CP), a chemotherapeutic agent. While AKI is a common occurrence amongst people who receive cisplatin (CP-AKI), the current risk assessment, intervention methods and understanding the role of magnesium in AKI, are either limited or understudied. OBJECTIVES: We aimed to build on previous CP-AKI risk prediction models, and establish a relationship between serum magnesium levels and AKI. Additionally, we used a feasibility study to test if intravenous magnesium sulfate in patients receiving intraoperative chemotherapy with cisplatin (HIOCC) for malignant mesothelioma can attenuate CP-AKI. This feasibility study was also used to determine a proper dosing regimen to achieve serum magnesium levels of 3 - 4.8 mg/dl. METHODS: We defined acute kidney injury as a 1.5-fold increase in serum creatine, or use of renal replacement therapy (RRT). Using clinical and demographic information from Memorial Sloan Kettering’s database, we conducted multivariable and univariable regression was used to identify the most significant demographic and clinical lab values. Using the information from the statistical analysis we built on previous risk prediction models for cisplatin associated kidney injury. Using the same statistical analysis, we further explored the relationship between serum magnesium values and AKI. In the feasibility study, we recruited patients from Brigham and Woman’s hospital who were receiving HIOCC treatment for mesothelioma. They received an infusion of intravenous magnesium sulfate during surgery. Serum magnesium levels were measured pre-operatively and post-operatively along with serum creatinine values. These were used to obtain pharmacokinetic information to further adjust the infusion rate in patients, lab values were also used to identify any AKI. CONCLUSION: A score-based model created using patient’s age, serum magnesium, albumin, hemoglobin, platelets, cisplatin dose and hypertension is predictive of cisplatin associated acute kidney injury. The feasibility study allowed us to inform phase 2 of an upcoming feasibility study that will include a bolus of 6g Mg/hr and an infusion of 2 g/hr after the bolus. This will work to increase the serum magnesium levels to the therapeutic range.

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Photodynamic therapy (PDT) is a form of cancer treatment involving light, a photosensitizer and oxygen, whereby the photosensitizer is preferentially taken up by tumour cells, excited when exposed to light of the appropriate wavelength, and generates cytotoxic excited singlet oxygen that damages and destroys cells. Photofrin is the only approved photosensitizer for clinical use in treating esophageal and early and late lung cancers in the U.S., Canada and several other countries. Despite its effectiveness in treating some tumour types, Photofrin use has some limitations and thus photosensitizers are continuously being studied to find more efficient ways of killing tumour cells. Previous reports have described the isolation of photodynamic therapy resistant human colon carcinoma HT29 cells. HT29/P14, HT29/All and HT29/N8 were isolated by repeated in vitro PDT treatment to the 1-10% survival level followed by regrowth of single surviving colonies using the photosensitizers Photofrin, Aluminium Phthalocyanine Tetrasulphonate (AlPcS4) and Nile Blue A respectively. These PDT resistant HT29 variants all display increased levels of BNip3, Bcl-2 and the heat shock protein 27 (Hsp 27), but decreased levels of Bax and the mutant HT29 p53 protein. Since mutant p53 and increased expression of Hsp27 and Bcl-2 and have been associated with resistance to various chemotherapeutic agents in some tumour cells, whereas Bax and BNip3 are potent inducers of apoptosis, it was considered of interest to examine the sensitivity of these PDT resistant HT29 variants to other cytotoxic agents. Cell sensitivity to ultraviolet (UV) A radiation (UV A), a mixture of UV A and UVB (UV AlB), UVC, or cisplatin was determined by a comparison of the D37 values for clonogenic survival in the variants compared to that in parental HT29 cells. The HT29 PDT resistant variants were not cross-resistant to cisplatin or UVC. In contrast, HT29/P14, HT29/All and HT29/N8 all showed a significant increase in cisplatin sensitivity, while HT29/All cells also showed a significant increase in UVC sensitivity. HT29/N8, and HT29/P14 both showed a significant increase in UVA resistance compared to HT29 cells whereas HT29/All did not. HT29/P14 was the only POT-resistant cell line significantly cross-resistant to UVA/B relative to HT29. While HT29/P14 and HT29/All both showed a slight increase in resistance to Photofrinmediated PDT compared to HT29/Parental, this increase was only significant for HT29/All. However, HT29/N8 was significantly more sensitive to Photofrin-mediated PDT than HT29/Parental. To complicate matters, clonogenic variability was observed amongst the two HT29 sources examined, since one of the original HT29 cell lines showed a significantly higher resistance to Photofrin-mediated PDT compared to the other parental HT29 cells that were used to derive the PDT -resistant cell lines. To examine if the differences in sensitivity of the PDT-resistant cell lines compared to parental HT29 cells in response to cisplatin and UV radiation were due to differences in DNA repair, host cell reactivation (HCR) experiments were performed with a UVC damaged B-galactosidase reporter gene from the adenovirus Ad5HCMVSp1LacZ. HCR ofthe UV-damaged reporter gene was reduced in HT29/All (the cell line most sensitive to UVC) compared to the parental HT29 cells at high multiplicities of infection of the virus. This suggests the possibility of a decreased DNA repair capacity for HT29/ A 11 cells. However, due to differences in cellular morphology between HT29 and HT29/All cells, as well as possible differences in expression of the reporter gene, it was inconclusive that the difference in HCR reflects a true difference in DNA repair between HT29 and HT29/All cells. Hsp27 over expression alone was not responsible for the increased cisplatin sensitivity of the HT29 PDT resistant variants since there was no correlation of Hsp27 protein expression levels to l/D37 (used as a measure of sensitivity), for the cisplatin colony survival assays. In addition, Hsp27 protein expression levels did not correlate with UVC, cisplatin or UV A sensitivity suggesting that Hsp27 may be uniquely involved in making cells more resistant to PDT. p53 but not BNip3 protein levels correlated with sensitivity of cells to UV A, whereas no correlation was observed between p53 or Hsp27 protein expression levels and UVC sensitivity. p53 and p21 protein levels were not altered in either parental HT29 or the HT29/P14 POT-resistant variant following UVC and cisplatin exposure, respectively. In addition, introduction of wild-type p53 (using infection of a replication deficient adenovirus vector encoding the wild-type p53 gene), into parental HT29 or the PDT -resistant HT29/P 14 variant, had no effect on cisplatin sensitivity compared to cells infected with a control adenovirus vector expressing the LacZ gene. Taken together, these results suggest that the increased sensitivity of the PDT resistant variants to cisplatin did not result from differences in p53-dependent cisplatininduced cell cycle arrest. A strong correlation of cellular cisplatin sensitivity to the ratio of BNip3 to p53 protein levels, suggests that alterations in the expression of several different genes, including a reduced expression of the mutant HT29 p53 protein and an increased expression of BNip3, contribute to the increased cisplatin sensitivity of the HT29 PDT resistant variants. It has been reported previously that apoptosis induced by BNip3 is significantly inhibited by both wild type and mutated p53. Since pro-apoptotic BNip3 is over expressed in all three PDT-resistant HT29 cell lines, and BNip3/p53 protein expression levels were correlated to cisplatin sensitivity, this suggests that cisplatin kills HT29 cells through a BNip3-mediated apoptotic pathway. / Thesis / Master of Science (MS)