Fatigue is the most prevalent and distressing symptom experienced by patients with advanced lung cancer and especially among those patients undergoing therapy. Advanced lung cancer and its associated symptoms can significantly impact the quality of life (QOL) of those who have the disease. The primary purpose of this study was to measure fatigue levels, characterize the fatigue experience, and assess for gender differences in perceptions of fatigue and QOL in patients with advanced lung cancer receiving chemotherapy. The secondary purpose of the study was to examine practice patterns in the ambulatory setting regarding the routine assessment of fatigue. The study was a secondary analysis of a larger study being conducted in the ambulatory clinics of a large, National Cancer Institute-designated comprehensive cancer center. The study sample consisted of fifty advanced lung cancer patients, 25 men and 25 women. Two self-report questionnaires, the Short-Form 36® (SF-36) Acute Version 1 and Fatigue Symptom Inventory (FSI), were completed by the subjects after receiving a single cycle of chemotherapy. A chart audit of the 50 subjects was performed assessing for provider documentation of fatigue assessment and method(s) utilized. Subjects ranged in age from 40 to 80, with a mean age of 62.4 years. Of the 50, 26 patients had Stage IV non-small cell lung cancer. A majority of the patients were receiving chemotherapy alone and had not received prior chemotherapy. The results of this study revealed no significant gender differences in fatigue severity, frequency, or interference levels. The study results also failed to confirm gender differences in QOL measures. The chart audit did reveal that the providers in this study did not consistently assess and document fatigue levels, with the nurses documenting less frequently than the physicians. The results of this study did suggest that fatigue levels and QOL are problematic for patients treated for lung cancer. In an effort to better assist patients and tailor plans of care, it is vital that practitioners, especially nurses, assess for fatigue in advanced lung cancer patients.

Background - Current guidelines suggest that all cancer patients with venous thrombosis be treated with long-term low molecular weight heparin. Whether treatment strategies should vary according to clinical characteristics remains unknown. // Systematic review - A systematic review was performed to determine current understanding of the association between malignancy characteristics in patients with cancer-associated VTE and the risk of VTE recurrence. Four retrospective and 6 prospective studies were included. They suggest that lung cancer, metastases, and adenocarcinomas confer an increased the risk of recurrence and breast cancer a low risk. // Survey - I performed survey to evaluate thrombosis experts’ opinion about the low risk of VTE recurrence they would consider acceptable for patients with cancer- associated thrombosis 103 specialists participated. 80% of respondents agreed that a risk of recurrent VTE during anticoagulation below 7% is low enough. 92% agreed that a CPR that categorizes risk of recurrence is relevant. // Retrospective Study - I performed a single retrospective cohort study to assess the feasibility of derivation of a CPR that stratifies VTE recurrence risk in patients with cancer–associated thrombosis. The study included 543 patients. A multivariate analysis selected female, lung cancer and prior history of VTE as high risk predictors and breast cancer and stage I disease as low risk. // Conclusion - Patients with cancer-associated thrombosis do have varying risks of recurrent VTE depending on clinical characteristics.

Background - Current guidelines suggest that all cancer patients with venous thrombosis be treated with long-term low molecular weight heparin. Whether treatment strategies should vary according to clinical characteristics remains unknown. // Systematic review - A systematic review was performed to determine current understanding of the association between malignancy characteristics in patients with cancer-associated VTE and the risk of VTE recurrence. Four retrospective and 6 prospective studies were included. They suggest that lung cancer, metastases, and adenocarcinomas confer an increased the risk of recurrence and breast cancer a low risk. // Survey - I performed survey to evaluate thrombosis experts’ opinion about the low risk of VTE recurrence they would consider acceptable for patients with cancer- associated thrombosis 103 specialists participated. 80% of respondents agreed that a risk of recurrent VTE during anticoagulation below 7% is low enough. 92% agreed that a CPR that categorizes risk of recurrence is relevant. // Retrospective Study - I performed a single retrospective cohort study to assess the feasibility of derivation of a CPR that stratifies VTE recurrence risk in patients with cancer–associated thrombosis. The study included 543 patients. A multivariate analysis selected female, lung cancer and prior history of VTE as high risk predictors and breast cancer and stage I disease as low risk. // Conclusion - Patients with cancer-associated thrombosis do have varying risks of recurrent VTE depending on clinical characteristics.

Hepatocarcinoma cancer (HCC) is one the most common visceral malignancies in Taiwan, which has a very high incidence and a devastatingly poor prognosis. BMP4, belonging to the TGF-£] super-family of proteins is a multifunctional cytokine, known to exert its biological effects through SMAD and non-SMAD dependent pathways and is also known to be involved in human carcinogenesis. However, the effects of the BMP4 signaling in liver carcinogenesis are not yet clearly defined. In this study, we first demonstrate that BMP4 and its receptor, BMPR1A, are over-expressed in a majority of primary HCC and promote the growth and migration of HCC cell lines in vitro. We also further identify that BMP4 can induce HCC CDK1 and cyclinB1 up-regulation to accelerate cell cycle progression. Our study indicates that the induction of HCC cell proliferation is independent on the SMAD signaling pathway, since Smad4 knockdown of BMP4 induced HCC cell lines still leads to the up-regulation of CDK1 and cyclinB1 expression in HCC. Using MEK kinase selective inhibitors, the induction of CDK1 and cyclinB1 mRNA and protein were shown to be dependent on the activation of MEK/ERK signaling. In vivo xenograft studies confirmed that the BMPR1A- knockdown cells were significantly less tumorigenic than control groups. Taken together, our findings show that the up-regulation of BMP4 and BMPR1A in HCC promote the proliferation and metastasis of HCC cells and that CDK1 and cyclinB1 are important, SMAD-independent molecular targets in BMP4 signaling pathways during the HCC tumorigenesis. We propose here that BMP4 signaling pathways may have potential as new therapeutic targets, in HCC treatment.

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Background - Current guidelines suggest that all cancer patients with venous thrombosis be treated with long-term low molecular weight heparin. Whether treatment strategies should vary according to clinical characteristics remains unknown. // Systematic review - A systematic review was performed to determine current understanding of the association between malignancy characteristics in patients with cancer-associated VTE and the risk of VTE recurrence. Four retrospective and 6 prospective studies were included. They suggest that lung cancer, metastases, and adenocarcinomas confer an increased the risk of recurrence and breast cancer a low risk. // Survey - I performed survey to evaluate thrombosis experts’ opinion about the low risk of VTE recurrence they would consider acceptable for patients with cancer- associated thrombosis 103 specialists participated. 80% of respondents agreed that a risk of recurrent VTE during anticoagulation below 7% is low enough. 92% agreed that a CPR that categorizes risk of recurrence is relevant. // Retrospective Study - I performed a single retrospective cohort study to assess the feasibility of derivation of a CPR that stratifies VTE recurrence risk in patients with cancer–associated thrombosis. The study included 543 patients. A multivariate analysis selected female, lung cancer and prior history of VTE as high risk predictors and breast cancer and stage I disease as low risk. // Conclusion - Patients with cancer-associated thrombosis do have varying risks of recurrent VTE depending on clinical characteristics.

Background - Current guidelines suggest that all cancer patients with venous thrombosis be treated with long-term low molecular weight heparin. Whether treatment strategies should vary according to clinical characteristics remains unknown. // Systematic review - A systematic review was performed to determine current understanding of the association between malignancy characteristics in patients with cancer-associated VTE and the risk of VTE recurrence. Four retrospective and 6 prospective studies were included. They suggest that lung cancer, metastases, and adenocarcinomas confer an increased the risk of recurrence and breast cancer a low risk. // Survey - I performed survey to evaluate thrombosis experts’ opinion about the low risk of VTE recurrence they would consider acceptable for patients with cancer- associated thrombosis 103 specialists participated. 80% of respondents agreed that a risk of recurrent VTE during anticoagulation below 7% is low enough. 92% agreed that a CPR that categorizes risk of recurrence is relevant. // Retrospective Study - I performed a single retrospective cohort study to assess the feasibility of derivation of a CPR that stratifies VTE recurrence risk in patients with cancer–associated thrombosis. The study included 543 patients. A multivariate analysis selected female, lung cancer and prior history of VTE as high risk predictors and breast cancer and stage I disease as low risk. // Conclusion - Patients with cancer-associated thrombosis do have varying risks of recurrent VTE depending on clinical characteristics.

Vitamin B12 and folate are necessary for bone marrow progenitor growth and division. Deficiencies are common in lymphoproliferative disorders due to increased demands of rapidly growing malignant cells. Isolated vitamin B12 deficiency is seen in 13% of these patients and may be their only manifestation. We present the case of vitamin B12 deficiency anemia due to an underlying malignancy that was discovered following supplementation. A 77-year-old nonsmoker female with chronic kidney disease and hypothyroidism presented to her internist with dyspnea, tachycardia and unintentional 7-pound weight loss. Age-appropriate cancer screenings were up-to-date. Physical exam was notable for an overweight female with tachycardia and trace ankle edema bilaterally. Electrocardiogram demonstrated sinus tachycardia. Labs were remarkable for hemoglobin 10.3 mg/dL (12.1 mg/dL one year ago) and serum B12/mL. She was started on intramuscular vitamin B12 supplementation. At her one-month follow-up, she reported debilitating gastrointestinal distress, rash, and fatigue lasting 5-6 days with every vitamin B12 injection. Physical exam was notable for 20-pound weight loss. Labs revealed hemoglobin 9.9 mg/dL despite serum B12 750 pg/mL and worsening kidney function with marked proteinuria. Additional work-up by primary team and subsequent Hematology & Oncology referral demonstrated elevated M-spike on urine protein electrophoresis and abnormal bone marrow biopsy suspicious for lymphoid malignancy. CT abdomen and whole body PET scan revealed increased uptake in the T12 vertebrae and multiple nodal basins consistent with stage IV lymphoma. Biopsy of vertebral body confirmed diffuse large B-cell lymphoma. The patient received one cycle of chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Her course was complicated by pathologic hip fracture requiring hospitalization and surgical repair. The patient died following cardiac arrest in the setting of septic shock from sigmoid colon perforation 7 months from initial presentation. Vitamin B12 and folate play critical roles in nucleic acid synthesis for bone marrow progenitors. Vitamin B12 deficiency arrests cell growth and division, leading to macrocytic anemia and various neuropsychiatric manifestations. It is a common diagnosis with numerous causes: autoantibodies to digestive proteins, poor dietary intake, small bowel malabsorption, etc. Diagnose with low hemoglobin (/dL or 13 mg/dL in non-pregnant women or men, respectively) and mean corpuscular volume >100 fL plus low serum B12 or elevated homocysteine and methyl-malonic acid levels. Replacement is given orally or intramuscularly. Vitamin B12 and folate deficiencies are found in lymphoproliferative disorders due to increased demands of rapidly growing malignant cells. Isolated vitamin B12 deficiency is seen in 13% of patients and may be the only clue. Replacement will not resolve their anemia. Physicians should monitor patients receiving supplementation. If anemia fails to improve or patients experience systemic symptoms, further investigation for lymphoid malignancies is warranted. This patient had dramatic deterioration with acceleration of underlying malignancy following vitamin B12 replacement. We believe supplementation enabled malignant lymphoid precursors to resume cell cycle growth and division. Only one report of vitamin B12 supplementation associated with unmasking a lymphoid malignancy exists in literature. Further research is needed to support whether supplementation can accelerate lymphoid malignancies.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22368号 / 医博第4609号 / 新制||医||1043(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 髙折 晃史, 教授 松田 文彦, 教授 滝田 順子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM