京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13219号 / 論医博第2166号 / 新制||医||1033(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 妹尾 浩, 教授 小川 修, 教授 戸口田 淳也 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第21699号 / 医科博第103号 / 新制||医科||7(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 妹尾 浩, 教授 渡邊 直樹, 教授 松原 和夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Chemotherapy, whether in combination therapies or as a monotherapy, is the standard treatment for most cancer subtypes. However, these regimens are administered systemically, resulting in poor pharmacokinetics and reducing the overall efficacy. Additionally, most chemotherapeutics, such as paclitaxel (PTX), are hydrophobic necessitating the use of solvents such as polyethoxylated castor oils, which are inherently toxic. Local delivery can mitigate these off-target toxicities while increasing the bioavailability of the payload. This was confirmed in studies by Dr. Paul Sugarbaker, showing that local paclitaxel, in the setting of multimodal therapy, can improve disease-free survival for peritoneal mesothelioma. However, this regimen is associated with high postoperative morbidities, due to the inherent toxicities. These studies establish the validity of local chemotherapy while also confirming the need for a novel delivery platform to allow for safe delivery of higher doses. Nanoparticles (NPs) have long been investigated to enhance chemotherapeutic delivery, increasing bioavailability, prolonging exposure durations, and mitigating off-target side effects. To address the unmet need for a local, sustained drug delivery system, this thesis discusses the formulation and validation of ultra-high loaded polymeric nanoparticles. Specifically, we use a biodegradable polymer comprised of glycerol, CO2, succinic acid, and paclitaxel building blocks, termed poly(1,2-glycerol carbonate)-graft-succinic acid-paclitaxel (PGC-PTX), to form NPs. By additionally entrapping free PTX within the NP core, we create ultra-high loaded “PGC-PTX+PTX NPs”. These NPs encapsulate over 75 wt% PTX, as the mass of the drug is greater than the mass of the carrier, and generate the desired greater initial release, while simultaneously maintaining therapeutic levels long-term due to cleavage of the chemically conjugated PTX over time. These nanoparticles demonstrate efficacy both in vitro and in vivo against murine models of both mesothelioma and metastatic breast cancer. Locally delivery ablates the primary tumor, while also decreasing metastasis to the lungs. This thesis validates the ability to deliver local chemotherapies utilizing the ultra- high loaded nanoparticles safely and effectively. Mesothelioma and breast cancer are both ideal models for local chemotherapy delivery due to their confined biology. However, more difficult biologies such as tumors in the GI tract suffer from significant fluid movement and peristalsis. Mucoadhesive materials, such as naturally occurring polysaccharides (chitosan and alginate) and positively charged synthetic polymers (poly(allylamine) hydrochloride and poly((2-dimethylamino)ethyl methacrylate) have been investigated for mucosal delivery, yet suffer from high variability and/or toxicities. Amine-functionalized poly-amido-saccharides (AmPASs) offer a unique solution, as they have exquisite control of molecular weight, high cationic charge density, are water soluble, and exhibit low toxicities due to their sugar backbone. Synthesizing an amphiphilic diblock copolymer was accomplished with AmPAS as the hydrophilic portion and poly(lactic acid) as the hydrophobic portion. When placed in aqueous conditions, this polymer forms 200nm diameter particles with a zeta potential of +25mV (mucoNPs). Utilizing a mini-emulsion technique, nanoparticles are loaded with ultra-high levels of paclitaxel, encapsulating both free drug, and drug conjugated to a hydrophobic core polymer (PGC-PTX). The mucoNPs release drug over the span of 28 days, with varying pharmacokinetics depending on encapsulation of free drug, conjugated drug, or both. These NPs rapidly enter OE19 and OE33 esophageal cancer cells, resulting in pronounced cytotoxicity when coupled with the ultra-high paclitaxel loading. Most importantly, the mucoNPs display greater adhesion to porcine gastric mucin and porcine esophageal tissue compared to non-mucoadhesive PEG nanoparticles. This work indicates the need for future in vivo studies with the mucoNPs, and ultimately enhance local mucosal delivery. / 2025-05-24T00:00:00Z

Boerhaave syndrome is a spontaneous rupture of the esophagus. It results from a sudden increase in esophageal pressure combined with negative intrathoracic pressure as seen with severe straining or vomiting. Esophageal perforation is extremely rare with an incidence of approximately 3.1 per 1,000,000 per year with a mortality rate estimated to be 20-50%. The rare occurrence and fatal nature of an esophageal perforation makes this syndrome a difficult yet important diagnosis to consider in the clinical setting. This case presents a previously healthy 47-year-old gentleman who presented to a local emergency department with syncope, vomiting, and chest pain sequentially. He reported a 24-hour history of dark stools followed by syncope, and when he regained consciousness he had three bouts of retching and expulsion of coffee-ground vomitus. Shortly after emesis, the patient developed severe and continuous pain located in his central chest that radiated to his back. Upon arrival to the hospital he was tachycardic. Blood tests revealed metabolic acidosis, increased white blood cell count, elevated lactate, and significant anemia. The patient’s hemoglobin was 7.7 gm/dL, a significant drop from the patient’s baseline level of 14. The patient received 1 unit of packed red blood cells and was sent for imaging studies. Chest X-ray and CT imaging revealed free air in the mediastinum, and a subsequent Gastrografin esophagogram study revealed a lower esophageal perforation proximal to gastroesophageal junction. The patient was rushed to the operating room for emergency surgery. An esophagogastroduodenoscopy showed no active bleeds and confirmed a distal mucosal defect suggestive of perforation. The surgery team then performed a left thoracotomy with intercostal muscle harvest and esophageal repair, with the patient needing an additional 4 units of packed red blood cells during surgery. He tolerated the surgery well and received appropriate post-op care in the ICU. A repeat Gastrografin and barium swallow esophagogram revealed no evidence of leak, strictures, or complications from the operation. A follow up CT image of the chest, abdomen, and pelvis was performed one month after hospital discharge, and results showed complete resolution of mediastinal air without evidence of esophageal leak. This case demonstrates how a spontaneous esophageal perforation can occur in previously healthy, middle aged patients with no significant GI history or identifiable risk factors. Given this information, clinicians should consider Boerhaave Syndrome when a patient of any age presents with chest pain after an episode of emesis.

Acute esophageal necrosis, commonly known as black esophagus, is a serious clinical condition that requires prompt diagnosis and management to improve morbidity and mortality. We present a 47-year-old woman who had this potentially lethal condition. The patient initially presented with hematemesis, and esophagogastroduodenoscopy at presentation showed diffuse esophageal ulcerations, erosions, and necrosis. During her admission, she required multiple blood transfusions for active bleeding, after which her clinical condition stabilized. Repeat esophagogastroduodenoscopy showed near-complete resolution of the earlier findings.

BACKGROUND High dose rate Intraluminal Brachytherapy (HDRILBT) is one of the most used palliative treatment options for advanced esophageal cancer. The present study evaluates the role of additional chemotherapy in improving dysphagia free survival (DFS) and overall survival (OS) in patients with inoperable advanced esophageal cancer treated with brachytherapy. MATERIAL and METHODS 132 patients with advanced metastatic esophageal cancer with total or near total dysphagia were given HDRILBT to a dose of 18 Gray (Gy) in 3 fractions on alternate days. Intraluminal brachytherapy alone was performed on 98 patients. 34 patients received Epirubicin, 5-Fluorouracil, and Cisplatin (ECF) chemotherapy regimen after HDRILBT. The mean age of the whole group was 65 years (HDRILBT-71.41, HDRILBT+ECF-59.98; p<0.0001). Male: Female was 101:31 (HDRILBT 72:26; HDRILBT +ECF 29:5; p>0.05). The location incidence was GEJ: Lower Esophagus: Mid Esophagus: Cervical Esophagus 24:81:17:5 respectively; for the whole group HDRILBT- 17:57:16:4; HDRILBT+ECF-7:24:1:1; p>0.05. 78 patients presented with co-morbidities (cardiac) (HDRILBT- 59; HDRILBT+ECF- 19; p>0.05). 74 patients presented with distant metastasis (54 with HDRILBT and 20 with HDRILBT+ECF; p>0.05). The ECOG scores were as follows 0:1:2:3:4 15:52:51:12:2 (HDRILBT- 10:35:41:10:2; HDRILBT+ECF- 5:17:10:2:0; p=0.0014). All patients completed 3 fractions of HDRILBT. 34 patients received additional chemotherapy with ECF regimen. Selection of patients was done by the medical oncologist. Statistical analysis of data was done using the SAS statistical analysis software system. Univariate and multivariate analysis was done using the log rang test. RESULTS Patients who received additional ECF were younger (p< 0.001) and with a better performance status than those who received HDRILBT alone (p=0.0014). Mean DFS was higher for patients who had further chemotherapy treatment (232 days) vs. patients who had HDRILBT only (155 days) (p>0.05). The mean OS for HDRILBT + ECF was 266 days (p = 0.0010) compare with HDRILBT alone which was 155 days, when the effect of 10 prognostic factors was analyzed for DFS and OS. Only additional ECF after brachytherapy impacted on DFS while age (p<0.001) and performance status (p=0.0014) impacted on overall survival on univariate analysis. On multivariate analysis tumor length and nodal presentation (p<0.000) impacted on OS. The incidence of stricture and fistulae were similar. Chemotherapy related side effects: gastrointestinal tract (25 patients), neurotoxicities (2) and nephrotoxicities (2) were seen as a result of 5-FU and Cisplatin respectively. 18 patients completed at least 3 cycles of ECF. CONCLUSION Additional chemotherapy with ECF after HDRILBT improves the DFS and OS in selected patients with advanced esophageal cancer. These patients tend to be younger with better performance status, small tumor length and nodal metastasis. The incidence of complications is similar with more than 50% patients completing at least 3 cycles of chemotherapy. / Thesis / Master of Science (MSc)

No description available.

No description available.

Background: At the time of endobronchial ultrasound (EBUS) staging, ultrasonographic features can be used to predict mediastinal lymph node (LN) malignancy. Predictive tools have been developed, however they have not gained widespread use due to lack of research demonstrating validity and reliability. We sought to develop a novel predictive tool, the Canada Score, capable of predicting malignancy and potentially guide LN biopsy decision making. Methods: We prospectively analyzed the ultrasonographic features of LNs from patients with NSCLC. Ultrasonographic features were identified by a single experienced endoscopist, this data was used to develop the Canada Score. Pathological specimens were used as the gold standard for determination of malignancy. Videos were then circulated to endoscopists across Canada, who were also asked to identify ultrasonographic features for each LN. Hosmer- Lemeshow test, logistic regression, receiver operator characteristic (ROC) curve, and Gwet’s AC1 analyses were used to test the performance, discriminatory capacity, and inter-rater reliability of the Canada Score. Results: A total of 300 LNs from 140 patients were analyzed by 12 endoscopists across 7 Canadian centres. Backwards elimination was used to create a multivariate model. Hosmer-Lemeshow test and ROC curves indicated the model was well-calibrated (chi2=11.86, p=0.1567) with good discriminatory power (c- statistic= 0.72 ±0.042, 95%CI: 0.64-0.80). Beta-coefficients were used to create a simplified score out of four. Evaluation of the tool showed that LNs scoring 3 or 4 had odds ratios of 15.17 (p<0.0001) and 50.56 (p=0.001), respectively for predicting malignancy. A score of 4/4 was associated with 99.59% specificity and a positive likelihood ratio of 22.78. Inter-rater reliability for a score ≥ 3 was 0.81 ± 0.02 (95%CI: 0.77-0.85). Conclusions: The Canada Score shows excellent performance in identifying malignant LN at the time of EBUS. A cut-off of ≥ 3 has the potential to inform decision-making regarding biopsy or repeat/mediastinoscopy if the initial results are inconclusive. / Thesis / Master of Science (MSc) / During lymph node staging for lung and esophageal cancer, specific features of lymph nodes can be seen. Using diagnostic tools these features can be used to predict whether a lymph node is cancerous or benign. However, many of these diagnostic tools are inaccurate or unreliable. To address this, this thesis aimed to develop a novel diagnostic tool based on lymph node features seen during staging procedures and determine its clinical usefulness and application to the wider lung and esophageal cancer population. This thesis also aimed to use improved methods to develop this diagnostic tool such that patient and clinician experiences would be significantly improved. The results of this thesis may contribute to a reduction in the number of repeat procedures required for patients undergoing staging prior to their treatment for lung and esophageal cancers.

Mob stocking is a variation of rotational stocking known for restricting a large number of animals to a small area before being moved to new grass after a few hours. This method allows a long (90-day) recovery period but was hypothesized to diminish the nutritional value of herbage relative to continuous and rotational stocking with lesser stocking density at similar stocking rates. This thesis summarizes two studies conducted in Blacksburg and Raphine, and in Steeles Tavern, VA, respectively, at a single beef cattle stocking rate of 12 animal unit months per hectare live body weight. The objectives were to: (1) compare the yield and nutritional value of herbage in pastures managed with three stocking methods, termed mob, rotational, and continuous stocking; (2) compare the abundance of seeded clover species among the stocking methods; and (3) estimate the nutritional value of herbage that is consumed by beef cattle during mob stocking using extrusa sampled from esophageally-cannulated animals. Analysis of standing herbage during two years produced several important findings. Although standing herbage mass was significantly greater in mob stocked pastures at Blacksburg and Raphine, aboveground net primary productivity in 2014 did not differ significantly among mob, rotational, and continuous stocking at any of the project locations. Herbage nutritive value did not differ significantly among stocking methods over two years at Blacksburg and Raphine; however, herbage from mob stocked pastures at Steeles Tavern contained significantly greater concentrations of crude protein in September and October relative to herbage from continuous- and rotationally-stocked pastures at those times. Differences in herbage mass likely contributed to significant differences in establishment of seeded clovers: red clover [Trifolium pratense L. Cinnamon Plus] establishment was similar among stocking methods but white clover [Trifolium repens L. Will] establishment was greater in continuously stocked pastures than mob and rotationally stocked pastures. Hand-clipped samples collected at Blacksburg in September 2014 significantly underestimated the crude protein content of the herbage selected by the steers, although the concentrations of fiber constituents in herbage did not differ significantly between clipped samples and esophageal samples. Although the nutritive value of the herbage on offer did not generally differ among stocking methods at this stocking rate, diet selected was at times less nutritious during mob stocking than continuous and rotational stocking methods. At this stocking rate, stocking method had less influence on pastures than seasonal variation in weather and plant maturity. / Master of Science