A novel hepatic-targeting system for therapeutic cytokines that delivers to the hepatic asialoglycoprotein receptor,but avoids receptor-mediated endocytosis

Purpose. To demonstrate the utilities of a synthetic low-affinity ligand ((Gal)₃) for the asialoglycoprotein receptor (ASGP-R) as a hepatic targeting device for therapeutic cytokines. Methods. The site-specific incorporation of (Gal)₃ or a typical high-affinity ligand (GalNAc)₃ into IL-2 was catalyzed by microbial transglutaminase. The anti-tumor activities, pharmacokinetic profiles and receptor-mediated endocytosis in hepatocytes of the ligand-IL-2 conjugates were examined in mouse. Results. The (Gal)₃ has approximately 50 times lower affinity to ASGP-R than (GalNAc)₃. Nevertheless, the antitumor effects were in the order of (Gal)₃—IL-2 > unmodified IL-2 > (GalNAc)₃—IL-2. The systemic elimination and the hepatic uptake of (GalNAc)₃—IL-2 were more rapid than (Gal)₃—IL-2. The ratio of the rate constant representing dissociation from the cell-surface receptor (k_off) to that representing endocytosis of the ligand (k_int) was greater for (Gal)₃—IL-2 than (GalNAc)₃—IL-2, suggesting that (Gal)₃—IL-2 preferably avoids internalization due to its lower affinity to the receptor. The simulation studies demonstrated that (Gal)₃—IL-2 was present in the hepatic extracellular space for a longer period than (GalNAc)₃ IL-2. Conclusions. The (Gal)₃ ligand increases the therapeutic efficacy of IL-2 by enhancing its exposure to the cell-surface. The k_off/k_int affects the targeting efficacy of the conjugates to ASGP-R.     

Heterogeneity of Proliferative Activity in Nodule-in-Nodule Lesions of Small Hepatocellular Carcinoma

Surgically resected small hepatocellular carcinomas showing "nodule-in-nodule'formation were analyzed in terms of cell proliferative activity. The analysis was achieved by successful immunohistochemical demonstration of proliferating cell nuclear antigen in formalin-fixed paraffin-embedded tissue sections. Eight nodules (up to 3 cm in diameter) examined were either atypical adenomatous hyperplasia or hepatocellular carcinoma of low histologic grade, containing a discrete inner nodular area composed of obvious hepatocellular carcinoma of higher histologic grade. In all cases, the proliferating cell nuclear antigen labeling index of the latter area was much higher than that of the former, which in turn was slightly higher than that of the non-cancerous liver of the patient in 6 cases. The data presented here provide supporting evidence that the successive emergence and expansion of a more rapidly proliferating subclone within a nodule result in the stepwise progression of malignancy of human hepatocellular carcinoma.     

The effect of maximal surgical cytoreduction on sensitivity to platinum-taxane chemotherapy and subsequent survival in patients with advanced ovarian cancer

ObjectivesLimited information exist about the frequency of micrometastases, their topographic distribution and prognostic impact in patients with cervical carcinoma (CX).MethodsLymph nodes of patients with surgically treated CX, FIGO IB to IIB, with pelvic lymph node involvement, were re-examined regarding the size of metastatic deposits, their topographic distribution within the pelvis. Lymph node status (pN0 vs. pN1mic = metastasis < 0.2 cm vs. pN1 = metastasis > 0.2 cm) was correlated to recurrence free (RFS) and overall survival (OS).Results31.4% of all patients (281/894) represented pelvic lymph node involvement. 22.2.% of the node positive ones showed micrometastases (pN1mic). Most commonly, obturator and internal nodes were affected by pN1mic, without any side differences. Patients with macrometastases (pN1) and micrometastases (pN1mic) represented significant reduced RFS-rate at 5-years (62% [95% CI: 54.2 to 69.8] for pN1 and 68.9% [95% CI: 55.5 to 82.4] for pN1mic) when compared to patients without metastatic disease (91.4% [95% CI: 89.0 to 93.8]; p < 0.001) The 5-years OS-rate was decreased in patients with metastatic disease (pN0: 86.6% [95% CI: 83.7 to 89.5], pN1mic: 63.8% [95% CI: 50.9 to 76.7], pN1: 48.2% [95% CI: 40.4 to 56.0]; p < 0.0001). These differences persisted in detailed analysis within these subgroups. In multivariate analysis, tumor stage, pelvic lymph node involvement and micrometastases were independent prognostic factors.ConclusionsA remarkable number of patients with CX show micrometastases within pelvic nodes. Micrometastatic disease represents an independent prognostic factor. So, all patients with pelvic lymph node involvement, including micrometastatic deposits, might be candidates for adjuvant treatment.     

Surgical and pathologic outcomes of fertility-sparing radical abdominal trachelectomy for FIGO stage IB1 cervical cancer

ObjectivesTo describe the surgical and pathologic findings of fertility-sparing radical abdominal trachelectomy using a standardized surgical technique, and report the rate of post-trachelectomy adjuvant therapy that results in permanent sterility.MethodsA prospectively maintained database of all patients with FIGO stage IB1 cervical cancer admitted to the operating room for planned fertility-sparing radical abdominal trachelectomy was analyzed. Sentinel node mapping was performed via cervical injection of Technetium and blue dye.ResultsBetween 6/2005 and 5/2008, 22 consecutive patients with FIGO stage IB1 cervical cancer underwent laparotomy for planned fertility-sparing radical abdominal trachelectomy. Median age was 33 years (range, 23–43). Histology included 13 (59%) with adenocarcinoma and 9 (41%) with squamous carcinoma. Lymph-vascular invasion was seen in 9 (41%) cases. Only 3 (14%) needed immediate completion radical hysterectomy due to intraoperative findings (2 for positive nodes, 1 for positive endocervical margin). Median number of nodes evaluated was 23 (range, 11–44); and 6 (27%) patients had positive pelvic nodes on final pathology — all received postoperative chemoradiation. Sixteen (73%) patients agreed to participate in sentinel node mapping which yielded a detection rate of 100%, sensitivity of 83%, specificity of 100% and false-negative rate of 17%. Eighteen of 19 (95%) patients who completed trachelectomy had a cerclage placed, and 9/22 (41%) patients had no residual cervical carcinoma on final pathology. Median time in the operating room was 298 min (range, 180–425). Median estimated blood loss was 250 ml (range, 50–700), and median hospital stay was 4 days (range, 3–6). No recurrences were noted at the time of this report.ConclusionsCervical adenocarcinoma and lymph-vascular invasion are common features of patients selected for radical abdominal trachelectomy. The majority of patients can undergo the operation successfully; however, nearly 32% of all selected cases will require hysterectomy or postoperative chemoradiation for oncologic reasons. Sentinel node mapping is useful but until lower false-negative rates are achieved total lymphadenectomy remains the gold standard. Investigating alternative fertility-sparing adjuvant therapy in node positive patients is needed.     

The impact of video-assisted thoracic surgery (VATS) in patients with suspected advanced ovarian malignancies and pleural effusions

OBJECTIVES: We previously reported our initial experience of patients with suspected advanced ovarian cancer and moderate to large pleural effusions who underwent video-assessed thoracic surgery (VATS) before planned abdominal exploration. The objective of this study was to report the surgical findings and management of patients who underwent VATS in an update of our experience. METHODS: We performed a retrospective review of all patients with suspected advanced ovarian cancer and moderate to large pleural effusions who underwent VATS for assessment of extent of intrathoracic disease at our institution between 6/01 and 8/05. RESULTS: Twenty-three patients with a median age of 61 years (range, 36-79) were identified. VATS was performed for right-sided effusions in 17 patients (74%), and a median of 1350 ml (400-3700 ml) of pleural fluid was drained. VATS demonstrated macroscopic disease in 15 (65%) patients, with nodules >1 cm in 11/15 (73%), and nodules <1 cm in 4/15 (27%). Macroscopic intrathoracic disease was found in 4/10 (40%) patients with negative cytology. Intrathoracic cytoreduction was performed in 3/11 patients (27%) with intrathoracic disease >1 cm. After VATS, 12/23 patients (52%) underwent primary surgical management, with cytoreduction to < or =1 cm achieved in 11/12 patients (92%). The other eleven patients received primary chemotherapy after undergoing diagnostic laparoscopy alone (4/11) or no further abdominal exploration (7/11). Nine of these patients proceeded to interval cytoreduction, while 2 had pathology demonstrating upper gastrointestinal and lymphoma primaries at the time of VATS. Final diagnosis of primary site of disease included: ovary, 14 (61%); endometrial, 2 (9%); dual ovarian/endometrial primaries, 1 (4%); fallopian tube, 1 (4%); primary peritoneal, 1 (4%); other, 4 (17%). Overall, findings at VATS altered primary surgical management in 11/23 (48%) patients. CONCLUSIONS: Sixty-five percent of patients with suspected advanced ovarian cancer and moderate to large pleural effusions had gross intrathoracic disease identified at VATS, with the majority (11/15, 73%) having disease >1 cm in diameter. Use of VATS allows for assessment of intrathoracic disease and may help identify candidates for primary cytoreductive surgery and possible intrathoracic cytoreduction versus neoadjuvant chemotherapy.