Oncolytic viruses and active immunotherapeutics have complementary mechanisms of action (MOA) that are both self amplifying in tumors, yet the impact of dose on subject outcome is unclear. JX-594 (Pexa-Vec) is an oncolytic and immunotherapeutic vaccinia virus. To determine the optimal JX-594 dose in subjects with advanced hepatocellular carcinoma (HCC), we conducted a randomized phase 2 dose-finding trial (n = 30). Radiologists infused low-or high-dose JX-594 into liver tumors (days 1, 15 and 29); infusions resulted in acute detectable intravascular JX-594 genomes. Objective intrahepatic Modified Response Evaluation Criteria in Solid Tumors (mRECIST) (15%) and Choi (62%) response rates and intrahepatic disease control (50%) were equivalent in injected and distant noninjected tumors at both doses. JX-594 replication and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression preceded the induction of anticancer immunity. In contrast to tumor response rate and immune endpoints, subject survival duration was significantly related to dose (median survival of 14.1 months compared to 6.7 months on the high and low dose, respectively; hazard ratio 0.39; P = 0.020). JX-594 demonstrated oncolytic and immunotherapy MOA, tumor responses and dose-related survival in individuals with HCC.

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Accurate prediction of future blood glucose trends has the potential to significantly improve glycemic regulation in type 1 diabetes patients. A model‐based controller for an artificial β‐cell, for example, would determine the most efficacious insulin dose for the current sampling interval given available input–output data and model predictions of the resultant glucose trajectory. The two inputs most influential to the glucose concentration are bolused insulin and meal carbohydrates, which in practice are often taken simultaneously and in a specified ratio. This linear dependence has adverse effects on the quality of linear dynamic models identified from such data. On the other hand, inputs with greater degrees of excitation may force the subject into extreme hypoglycemia or hyperglycemia, and thus may be clinically unacceptable. Inputs with good excitation that do not endanger the subject are shown to result in models that can predict glucose trends reasonably accurately, 1–2 h ahead. © 2009 American Institute of Chemical Engineers AIChE J, 2009

The magnitude of EBL during HCC resection is related to biologic characteristics of the tumor as well as the extent of surgery. Increased intraoperative blood loss during HCC resection is an independent prognostic factor for tumor recurrence and death.

Partial hepatectomy in patients with early HCC who are otherwise eligible for transplantation can be performed with minimal morbidity and can achieve comparable 5-year survival to that reported for liver transplantation. Resection should be considered the standard therapy for patients with HCC who have adequate liver reserve.

Preoperative radiation (RT) and chemotherapy improve outcome in patients with locally advanced rectal adenocarcinoma and, therefore, have been used increasingly in patient management. The histopathologic alterations in postirradiated rectal adenocarcinoma and their prognostic significance have not been fully characterized. In this study, detailed analyses of morphologic alterations of stromal and tumor cells were performed in a series of 66 posttreatment rectal carcinomas, and the pathologic findings were correlated with long-term outcome. All tumors were locally advanced, with a bulky and/or tethered tumor or endorectal ultrasound or magnetic resonance imaging evidence of T3-4 and / or N1 disease. All patients were treated at one institution with preoperative RT to the pelvis (at least 4500 cGy) with or without concurrent 5-fluorouracil (5-FU)-based chemotherapy 4 to 7 weeks prior to surgical resection. Pathologic assessment showed some treatment response in all patients. Nine patients (13.4%) had complete response, and 8 (11.9%) had near-complete response (> 95% of the tumor replaced by fibroinflammatory tissue). Salient morphologic features included marked fibrosis with or without prominent inflammatory cells replacing neoplastic glands; lack of active tumor necrosis; increased mucin production and mucin pools; marked cytoplasmic eosinophilia, often in combination with marked nuclear atypia but without active mitoses in tumor cells showing treatment effect; endocrine tumor phenotype; and retention of mucosal adenoma in the presence of tumor regression within the bowel wall. With a median follow-up of 69 months, the estimated 5-year recurrence-free survival (RFS) for the entire group was 79%. By univariate analysis, the residual tumor stage (P < 0.05) and reduction of pretreatment T stage (P = 0.002) significantly correlated with RFS, as did pN stage (P = 0.002) and lymphovascular invasion (P = 0.008). The extent of treatment response did not correlate with RFS (P = 0.4). However, patients with a treatment response > or = 95% seemed to fare better than those with a treatment response < 95% (marginally significant difference in RFS, P = 0.057). Univariate and multivariate analyses identified the following morphologic patterns that were significantly associated with a reduced RFS independent of other risk factors: a fibrotic-type stromal response with minimal inflammatory infiltrates (P = 0.001) and absence of surface ulceration (P = 0.026). Our study represents the first detailed morphologic assessment of rectal carcinomas that have been subjected to long course preoperative RT and chemotherapy. Our results demonstrate distinct morphologic features in treated rectal carcinomas that are prognostically relevant.

ObjectiveTo determine whether selected clinicopathologic factors, including the extent of pathologic response to preoperative radiation and chemotherapy (RT Ϯ chemo), have an impact on long-term recurrence-free survival (RFS) in patients with locally advanced primary rectal cancer after optimal multimodality therapy. Summary Background DataAlthough complete pathologic response to preoperative RT Ϯ chemo has been detected in up to 30% of rectal cancers, its significance on long-term outcome has not been widely reported. Previous retrospective studies evaluating clinical outcome in patients with complete or near-complete pathologic response documented good prognosis in this population but were limited by median follow-up in the range of 2 to 3 years. MethodsSixty-nine patients with locally advanced (T 3-4 and/or N 1 ) primary rectal cancer were prospectively identified. All were treated at one institution with preoperative RT to the pelvis (at least 4,500 cGy). Forty patients received concurrent preoperative 5-fluorouracil-based chemotherapy and 27 received both pre-and postoperative chemotherapy. Patients underwent resection 4 to 7 weeks after completion of RT. TNM stage, angiolymphatic or perineural invasion, and extent of response to preoperative RT Ϯ chemo were determined by pathologic evaluation. Adverse pathologic features were defined as the presence of angiolymphatic and/or perineural invasion. RFS at 5 years was determined by the Kaplan-Meier method. ResultsWith a median follow-up of 69 months, 5-year RFS was 79%. RFS was significantly worse for patients with aggressive pathologic features and positive nodal status identified in the postirradiated surgical specimen. Risk ratios for RFS were 3.68 for the presence of aggressive pathologic features and 4.64 for node-positive rectal cancers. In patients with greater than 95% rectal cancer response to preoperative RT Ϯ chemo, only one patient has died as a consequence of cancer, another has died of an unrelated cause, and the remainder were free of disease with a minimum follow-up of 47 months. ConclusionsThese data suggest that a marked response to preoperative RT Ϯ chemo may be associated with good long-term outcome but was not predictive of RFS. The presence of poor histopathologic features and positive nodal status are the most important prognostic indicators after neoadjuvant therapy.In patients with locally advanced (T 3-4 and/or N 1 ) rectal cancer, combined modality adjuvant therapy improves local control and survival.1 Although the timing, dosage, and method of delivery are controversial, patients receiving preoperative radiation and chemotherapy (RT Ϯ chemo)

BACKGROUND. Surgical resection for large (Ͼ 10 cm) hepatocellular carcinoma (HCC) is believed by many to be ineffective. The objective of the current study was to review the outcome of partial hepatectomy in patients with large HCC. METHODS. Between 1985 and 2002, 193 consecutive patients who underwent partial hepatectomy for HCC were identified from a prospective database. The 82 patients with tumors Ͼ 10 cm were compared with the remaining 111 patients with Յ 10 cm tumors. Clinicopathologic features were analyzed and prognostic factors were evaluated by univariate and multivariate analysis. RESULTS. The 5-year overall survival for patients with large HCC was 33% with a median of 32 months. Patients with Յ 10 cm tumors had similar survival. Furthermore, there was no significant difference between the groups in operative mortality (2% in large HCC vs. 6%) or recurrence rate. In patients with large HCC, vascular invasion by tumor and intraoperative blood loss Ͼ 2 liters predicted overall survival on multivariate analysis. CONCLUSIONS. Partial hepatectomy is safe for patients with large HCC. In selected patients with large tumors, resection achieves similar overall survival and recurrence-free survival to that of patients with smaller tumors. Minimizing intraoperative blood loss appears to be critical for favorable long-term outcome in patients