Antitumor effects of systemic and local immunization with a CTL-directed peptide in combination with a local injection of OK-432.

PURPOSE: The accumulation of T cells into the tumor site is crucial for the elicitation of in vivo antitumor effects after cancer vaccination. In this study, we investigated the antitumor effects and associated mechanisms of action that were induced by systemic and local immunization with a CTL-directed peptide in combination with a peritumoral injection of a streptococcal preparation, OK-432. EXPERIMENTAL DESIGN AND RESULTS: The human SART3(315-323) peptide, which has the potential to induce human leukocyte antigen-A24-restricted CTLs, not only has the same amino acid sequence as the mouse SART3, but also has the capacity for binding to H-2K(d) molecules. Therefore, the SART3(315-323) peptide could be used as a tumor antigen-derived peptide in H-2(d) mice. Systemic immunization with the SART3(315-323) peptide and the subsequent peritumoral injection of both the SART3(315-323) peptide and OK-432 effectively induced peptide-specific and colon26 carcinoma-reactive CTLs in BALB/c mice. The combination therapy suppressed the growth of s.c. established colon26 carcinoma. The accumulation of both CD8(+) and CD4(+) T cells into the tumor site was more apparent in mice treated with the combination therapy than in those treated with other protocols. In addition, the level of IgG reactive to the administered SART3(315-323) peptide increased in mice that were treated with the combination therapy. CONCLUSION: These results indicate that antitumor effects could be efficiently induced by a combination therapy that included systemic and local immunization with a CTL-directed peptide together with a local injection of OK-432.     

Changes in left ventricular end-diastolic area, end-systolic wall stress, and fractional area change during anesthetic induction with propofol or thiamylal

Purpose. To elucidate the mechanisms of the more profound hypotensive effects of propofol relative to thiamylal, we monitored changes in left ventricular (LV) preload, afterload, and contractility during the course of anesthetic induction with propofol and thiamylal. Methods. Thirty-two patients (ASA I) were randomly assigned into two groups and injected with propofol (2 mg·kg⁻¹) or thiamylal (4 mg·kg⁻¹) as anesthetic induction agents. Transthoracic echocardiography (TTE) was used to assess LV performance before and during induction by the two anesthetics. The LV end-diastolic area (EDA) and LV end-systolic wall stress (ESWS) were used as indices of LV preload and LV afterload, respectively, while LV contractility was assessed by the fractional area change (FAC). Results. Both propofol and thiamylal significantly reduced EDA and ESWS without significant change in FAC. Propofol-induced reductions in EDA and ESWS were significantly greater than those of thiamylal. Conclusion. The more profound hypotension observed during induction of anesthesia with propofol is due to the greater decrease in preload and afterload than with thiamylal, but not to a decrease in LV contractility. Received: December 8, 1999 / Accepted: April 19, 2000     

Intestinal alkalization as a possible preventive mechanism in irinotecan (CPT-11)-induced diarrhea.

The therapeutic efficacy of irinotecan (CPT-11), a DNA topoisomerase inhibitor, is often limited by the induction of severe late-onset diarrhea. This prodrug and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), have a labile alpha-hydroxy-lactone ring that undergoes pH-dependent reversible hydrolysis. At physiological pH and higher, equilibrium favors the less toxic carboxylate form, whereas at acidic pH, the more potent lactone form is favored. We have reported previously that the initial uptake rate of CPT-11 and SN-38 by intestinal cells was significantly different between the respective lactone and carboxylate form. Results from the present study in HT-29 cells further demonstrate the correlation between the CPT-11/SN-38 initial uptake rate and the induced toxicity, cell cycle alteration, apoptosis, and colony-forming efficiency. The exposure of HT-29 cells to SN-38 for a limited period of time (<2 h) was sufficient to induce these events. Because the decreased initial uptake of SN-38 carboxylate resulted in a reduced cellular toxicity, we postulated that the CPT-11-induced diarrhea was preventable by influencing the equilibrium toward the carboxylate form and, thus, reducing its intestinal uptake. In the golden Syrian hamster model, p.o. sodium bicarbonate supplementation (5 mg/ml in drinking water) led to alkalization of the intestinal contents. In addition, this alkalization resulted in the reduction of the histopathological damage to the mucosa of the small and large intestine, as well as a 20% reduction of the intestinal SN-38 lactone concentration of animals receiving CPT-11 (20-50 mg/kg x 7 days). Taken together, these results from in vitro and in vivo studies support intestinal alkalization by sodium bicarbonate supplementation as a preventive mechanism against CPT-11-induced diarrhea. In addition, this provides a strong rationale for the usage of this measure as an adjunct to CPT-11 treatment.     

Registration accuracy and possible migration of internal fiducial gold marker implanted in prostate and liver treated with real-time tumor-tracking radiation therapy (RTRT).

BACKGROUND AND PURPOSE: We have developed a linear accelerator synchronized with a fluoroscopic real-time tumor-tracking system to reduce errors due to setup and organ motion. In the real-time tumor-tracking radiation therapy (RTRT) system, the accuracy of tumor tracking depends on the registration of the marker's coordinates. The registration accuracy and possible migration of the internal fiducial gold marker implanted into prostate and liver was investigated.MATERIALS AND METHODS: Internal fiducial gold markers were implanted in 14 patients with prostate cancer and four patients with liver tumors. Computed tomography (CT) was carried out as a part of treatment planning in the 18 patients. A total of 72 follow-up CT scans were taken. We calculated the relative relationship between the coordinates of the center of mass (CM) of the organs and those of the marker. The discrepancy in the CM coordinates during a follow-up CT compared to those recorded during the planning CT was used to study possible marker migration.RESULTS: The standard deviation (SD) of interobserver variations in the CM coordinates was within 2.0 and 0.4 mm for the organ and the marker, respectively, in seven observers. Assuming that organs do not shrink, grow, or rotate, the maximum SD of migration error in each direction was estimated to be less than 2.5 and 2.0 mm for liver and prostate, respectively. There was no correlation between the marker position and the time after implantation.CONCLUSION: The degree of possible migration of the internal fiducial marker was within the limits of accuracy of the CT measurement. Most of the marker movement can be attributed to the measurement uncertainty, which also influences registration in actual treatment planning. Thus, even with the gold marker and RTRT system, a planning target volume margin should be used to account for registration uncertainty.     

Severe complications of mediastinal pancreatic pseudocyst: report of esophagobronchial fistula and hemothorax

We report two patients with alcoholic pancreatic pseudocyst which communicated to the mediastinal space through the aortic hiatus, in one patient resulting in hypotensive shock due to hemothorax, and in the other, resulting in esophagobronchial fistula via the mediastinal cyst. The first patient was successfully treated by radical resection of the pancreatic body and tail, and the spleen, with an ultrasonic scalpel, although inflammatory changes caused by pancreatitis were so prominent that the splenic vein was occluded. The second patient could not be treated surgically, because the superior mesenteric vein had been occluded by chronic pancreatitis; he died of respiratory failure and sepsis due to aspiration pneumonia, despite receiving medical treatment. Received for publication on June 14, 1999; accepted on Aug. 10, 1999     

Composite Tumor with Papillary Adenocarcinoma and Squamous Cell Carcinoma of the Esophagus: Report of a Case

(Received for publication on Mar. 2, 1999; accepted on Nov. 11, 1999)     

下咽癌肿瘤及转移淋巴结中VEGF、PDGF和MVD的表达及意义

目的 :探讨下咽癌转移淋巴结与原发灶肿瘤的血管内皮生长因子 (VEGF)、血小板来源的内皮生长因子 (PDGF/dThdPase)、Ⅷ因子测定微血管密度 (MVD)表达的差异。方法 :应用免疫组织化学LASB法检测 4 8例下咽鳞状细胞癌转移淋巴结与原发灶中VEGF、PDGF/dThdPase、MVD的表达差异。结果 :原发灶中VEGF平均阳性标识率为 2 5 .38% ,淋巴结中为 2 1.5 2 % ,两者差异无显著性意义。PDGF/dThdPase阳性标识率为2 9.5 9% ,淋巴结中为 4 0 .75 % ,两者差异有极显著性意义 (P <0 .0 1)。MVD测定均数为 34.9,淋巴结中均数为2 1.2 ,两者差异有极显著性意义 (P <0 .0 1)。以高低分组记数后VEGF在病理分级、生存与死亡组中有显著性差异 ;MVD在生存与死亡组、早晚期分组、T分期组中差异有显著性意义 (P <0 .0 5 )。以标示指数和血管计数 ,VEGF、PDGF表达与MVD呈正相关。结论 :MVD、VEGF可作为临床预测下咽癌颈淋巴结转移及预后的重要参考指标 ;PDGF在淋巴结中表达明显高于原发灶 ,MVD在原发灶中表达明显高于淋巴结     

Chronic renal allograft nephropathy

Chronic rejection/chronic allograft nephropathy is the most prevalent cause of renal graft loss after the first year post-transplant. Chronic rejection/chronic allograft nephropathy is characterized by a slow progressive deterioration of graft function, often in combination with proteinuria and hypertension. Both immunologic and non-immunologic factors play key roles in the pathogenesis of chronic allograft nephropathy. Acute rejection episodes are the most prevalent risk factor for chronic rejection. Many risk factors for chronic allograft nephropathy have been identified, such as delayed graft function, nephron-dosing mismatch, repeated acute rejection episodes, and pathologically severe rejection. However, the precise pathogenesis of chronic allograft nephropathy remains elusive. The differential diagnosis of immunologically mediated chronic rejection and chronic rejection caused by non-immunologic factors is usually not possible using clinical parameters. The histopathologic findings of chronic allograft nephropathy are progressive interstitial fibrosis and remodelling of the vascular wall, and these findings are nonspecific. However, typical chronic transplant glomerulopathy, which affects glomerular tufts, as well as the multilayering of the peritubular capillary basement membrane, are characteristic of immunologic chronic rejection. Furthermore, in long-surviving patient with an allograft treated with a potent immunosuppressive agent, a calcineurin inhibitor, two or more concomitant independent lesions often develop. Therefore, the term "chronic allograft nephropathy" may be clinically preferable to "chronic rejection" to describe the gradual decline in graft function months or years after transplantation, in the absence of a well defined mechanism of graft dysfunction. The most effective way to prevent chronic allograft nephropathy is to avoid any kind of graft damage via either immunologic or non-immunologic mechanisms. Received: April 1, 2000 / Accepted: May 2, 2000     

Off-pump coronary artery bypass grafting via partial sternotomy. An alternative to left anterior small thoracotomy.

Four patients, who were considered to be inappropriate candidates for left anterior small thoracotomy, underwent off-pump coronary artery bypass grafting via partial sternotomy. Under a median skin incision over the lower half of the sternum, the sternum below the second rib was cut in an "inverted L" (or "C") shape. Without cardiopulmonary bypass, the left internal thoracic artery was anastomosed to the left anterior descending artery in all patients, and a saphenous vein graft was anastomosed to the right coronary artery in one of them. Partial sternotomy has some advantages as an alternative to left anterior small thoracotomy, in that it enables multiple-bypass grafting without cardiopulmonary bypass and conversion to cardiopulmonary bypass, should it be come necessary, would be relatively uncomplicated.     

Conflict of intentions due to callosal disconnection

OBJECTIVES: Three patients with callosal syndrome manifested a peculiar symptom in that they were unable to perform intended whole body actions because another intention emerged in competition with the original one. Attempts were made to clarify the symptomatology of this manifestation and its possible mechanism is discussed. METHODS: The three patients are described and previous reports on patients with callosal damage were reviewed. Four additional patients with similar symptoms were found and the clinical features common to all seven patients were examined. RESULTS: This symptom could not be attributed to unilateral movement disorders such as unilateral apraxia, intermanual conflict, or compulsive manipulation of tools. The manifestations included marked hesitation in initiating actions, interruption of actions, repetitive actions, and performance of unintended actions with difficulty in correcting them. All patients, except one, had a lesion in the posterior half of the body of the corpus callosum, and there was no significant involvement of the cerebral cortex. The symptom became manifest later than 4 weeks after callosal damage. It occurred during spontaneous actions, but not during well automated actions nor when following instructions. CONCLUSION: This symptom, tentatively named "conflict of intentions", can be regarded as a fragment of diagonistic dyspraxia originally described by Akelaitis, although it can occur independently of intermanual conflict. Normally, the right and left cerebral hemispheres may be complementarily modifying automated whole body actions in order to adapt behaviour to changes of the environment as well as to the intention. Partial callosal disconnection without significant cortical involvement would exaggerate the disparity between the role of each hemisphere through the reorganisation of neural systems after callosal damage. Such double, often contrary, behavioural tendencies may sometimes simultaneously enter the patient's awareness.