Extremes of body mass index and postoperative complications after esophagectomy.

Obesity has been variously associated with reduced or similar rates of postoperative complications compared to normal weight patients undergoing esophagectomy for cancer. In contrast, little is known about esophagectomy risks in the underweight population. The relationship between the extremes of body mass index (BMI) and postoperative complications after esophagectomy was evaluated. Consecutive esophagectomy patients (2000-2013) were reviewed. The patients were stratified based on BMI at the time of diagnosis: underweight (<18.5), normal (18.5-24.9), overweight (25-29.9), obese I (30-34.9), and obese II or III (≥35). Hospital length of stay as well as postoperative complications and their accordion severity grading were evaluated according to the BMI category. Of 388 patients, 78.6% were male with a median age of 62 years at the time of operation. Pathologic cancer stage was 0 to I in 53%. BMI distribution was as follows: 5.6% underweight, 28.7% normal, 31.4% overweight, 22.8% obese I, and 11.5% obese II or III. Performance status was 0 or 1 in 99.2%. Compared to normal BMI patients, underweight patients had increased pulmonary complications (odds ratio (OR) 3.32, P = 0.014) and increased other postoperative complications (OR 3.00, P = 0.043). Patients who were overweight did not have increased complications compared to normal BMI patients. BMI groups did not differ in mortality rates or complication accordion severity grading. Hospital length of stay trended toward a longer duration in the underweight population (P = 0.06). Underweight patients are at increased risk for postoperative pulmonary and other complications. Underweight patients may benefit from preoperative nutritional repletion and mitigation for sarcopenia. Aggressive postoperative pulmonary care may help reduce complications in these patients. In contrast, the operative risk in overweight and obese patients is similar to normal BMI patients.

Basal Tumor Cell Isolation and Patient-Derived Xenograft Engraftment Identify High-Risk Clinical Bladder Cancers.

Strategies to identify tumors at highest risk for treatment failure are currently under investigation for patients with bladder cancer. We demonstrate that flow cytometric detection of poorly differentiated basal tumor cells (BTCs), as defined by the co-expression of CD90, CD44 and CD49f, directly from patients with early stage tumors (T1-T2 and N0) and patient-derived xenograft (PDX) engraftment in locally advanced tumors (T3-T4 or N+) predict poor prognosis in patients with bladder cancer. Comparative transcriptomic analysis of bladder tumor cells isolated from PDXs indicates unique patterns of gene expression during bladder tumor cell differentiation. We found cell division cycle 25C (CDC25C) overexpression in poorly differentiated BTCs and determined that CDC25C expression predicts adverse survival independent of standard clinical and pathologic features in bladder cancer patients. Taken together, our findings support the utility of BTCs and bladder cancer PDX models in the discovery of novel molecular targets and predictive biomarkers for personalizing oncology care for patients.

Consensus Conference on North American Training in Hepatopancreaticobiliary Surgery: A Review of the Conference and Presentation of Consensus Statements.

The findings and recommendations of the North American consensus conference on training in hepatopancreaticobiliary (HPB) surgery held in October 2014 are presented. The conference was hosted by the Society for Surgical Oncology (SSO), the Americas Hepato-Pancreatico-Biliary Association (AHPBA), and the American Society of Transplant Surgeons (ASTS). The current state of training in HPB surgery in North America was defined through three pathways-HPB, surgical oncology, and solid organ transplant fellowships. Consensus regarding programmatic requirements included establishment of minimum case volumes and inclusion of quality metrics. Formative assessment, using milestones as a framework and inclusive of both operative and nonoperative skills, must be present. Specific core HPB cases should be defined and used for evaluation of operative skills. The conference concluded with a focus on the optimal means to perform summative assessment to evaluate the individual fellow completing a fellowship in HPB surgery. Presentations from the hospital perspective and the American Board of Surgery led to consensus that summative assessment was desired by the public and the hospital systems and should occur in a uniform but possibly modular manner for all HPB fellowship pathways. A task force composed of representatives of the SSO, AHPBA, and ASTS are charged with implementation of the consensus statements emanating from this consensus conference.

Oncogenic CXCL10 signalling drives metastasis development and poor clinical outcome.

BACKGROUND: The CXCL10/CXCR3 signalling mediates paracrine interactions between tumour and stromal cells that govern leukocyte trafficking and angiogenesis. Emerging data implicate noncanonical CXCL10/CXCR3 signalling in tumourigenesis and metastasis. However, little is known regarding the role for autocrine CXCL10/CXCR3 signalling in regulating the metastatic potential of individual tumour clones. METHODS: We performed transcriptomic and cytokine profiling to characterise the functions of CXCL10 and CXCR3 in tumour cells with different metastatic abilities. We modulated the expression of the CXCL10/CXCR3 pathway using shRNA-mediated silencing in both in vitro and in vivo models of B16F1 melanoma. In addition, we examined the expression of CXCL10 and CXCR3 and their associations with clinical outcomes in clinical data sets derived from over 670 patients with melanoma and colon and renal cell carcinomas. RESULTS: We identified a critical role for autocrine CXCL10/CXCR3 signalling in promoting tumour cell growth, motility and metastasis. Analysis of publicly available clinical data sets demonstrated that coexpression of CXCL10 and CXCR3 predicted an increased metastatic potential and was associated with early metastatic disease progression and poor overall survival. CONCLUSION: These findings support the potential for CXCL10/CXCR3 coexpression as a predictor of metastatic recurrence and point towards a role for targeting of this oncogenic axis in the treatment of metastatic disease.

Multicenter phase II trial of adjuvant therapy for resected pancreatic cancer using cisplatin, 5-fluorouracil, and interferon-alfa-2b-based chemoradiation: ACOSOG Trial Z05031.

BACKGROUND: The American College of Surgeons Oncology Group sought to confirm the efficacy of a novel interferon-based chemoradiation regimen in a multicenter phase II trial. PATIENTS AND METHODS: Patients with resected (R0/R1) adenocarcinoma of the pancreatic head were treated with adjuvant interferon-alfa-2b (3 million units s.c. on days 1, 3, and 5 of each week for 5.5 weeks), cisplatin (30 mg/m(2) i.v. weekly for 6 weeks), and continuous infusion 5-fluorouracil (5-FU; 175 mg·m(2)/day for 38 days) concurrently with external-beam radiation (50.4 Gy). Chemoradiation was followed by two 6-week courses of continuous infusion 5-FU (200 mg·m(2)/day). The primary study end point was 18-month overall survival from protocol enrollment (OS18); an OS18 ≥65% was considered a positive study outcome. RESULTS: Eighty-nine patients were enrolled. Eighty-four patients were assessable for toxicity. The all-cause grade ≥3 toxicity rate was 95% (80 patients) during therapy. No long-term toxicity or toxicity-related deaths were noted. At 36-month median follow-up, the OS18 was 69% [95% confidence interval (CI) 60% to 80%]; the median disease-free survival and overall survival were 14.1 months (95% CI 11.0-20.1 months) and 25.4 months (95% CI 23.4-34.1 months), respectively. CONCLUSIONS: Notwithstanding promising multi-institutional efficacy results, further development of this regimen will require additional modifications to mitigate toxic effects.

Translational strategies exploiting TNF-alpha that sensitize tumors to radiation therapy.

TNFerade is a radioinducible adenoviral vector expressing tumor necrosis factor-alpha (TNF-alpha) (Ad.Egr-TNF) currently in a phase III trial for inoperable pancreatic cancer. We studied B16-F1 melanoma tumors in TNF receptor wild-type (C57BL/6) and deficient (TNFR1,2-/- and TNFR1-/-) mice. Ad.Egr-TNF+IR inhibited tumor growth compared with IR in C57BL/6 but not in receptor-deficient mice. Tumors resistant to TNF-alpha were also sensitive to Ad.Egr-TNF+IR in C57BL/6 mice. Ad.Egr-TNF+IR produced an increase in tumor-associated endothelial cell apoptosis not observed in receptor-deficient animals. Also, B16-F1 tumors in mice with germline deletions of TNFR1,2, TNFR1 or TNF-alpha, or in mice receiving anti-TNF-alpha exhibited radiosensitivity. These results show that tumor-associated endothelium is the principal target for Ad.Egr-TNF radiosensitization and implicate TNF-alpha signaling in tumor radiosensitivity.

Resveratrol is an effective inducer of CArG-driven TNF-alpha gene therapy.

We report the anticarcinogenic, anti-aging polyphenol resveratrol activates the radio- and chemo-inducible cancer gene therapy vector Ad.Egr.TNF, a replication-deficient adenovirus that expresses human tumor necrosis factor alpha (TNF-alpha) under control of the Egr-1 promoter. Like ionizing radiation or chemotherapeutic agents previously shown to activate Ad.Egr.TNF, resveratrol also induces Egr-1 expression from its chromosomal locus with a possible role for Egr-1 promoter CC(A+T)richGG sequences in the expression of TNF-alpha. Resveratrol induction of TNF-alpha in Ad.Egr.TNF-infected tumor xenografts demonstrated antitumor response in human and rat tumor models comparable to that of radio- or chemotherapy-induced TNF-alpha. Although sirtuins are known targets of resveratrol, in vitro inhibition of SIRT1 activity did not abrogate resveratrol induction of Egr-1 expression. This suggests that SIRT1 is not essential to mediate resveratrol induction of Egr-1. Nevertheless, control of transgene expression via resveratrol activation of Egr-1 may extend use of Ad.Egr.TNF to patients intolerant of radiation or cytotoxic therapy and offer a novel tool for development of other inducible gene therapies.

Ionizing radiation: a genetic switch for cancer therapy.

Gene therapy of cancer represents a promising but challenging area of therapeutic research. The discovery of radiation-inducible genes led to the concept and development of radiation-targeted gene therapy. In this approach, promoters of radiation-inducible genes are used to drive transcription of transgenes in the response to radiation. Constructs in which the radiation-inducible promoter elements activate a transgene encoding a cytotoxic protein are delivered to tumors by adenoviral vectors. The tumoricidal effects are then localized temporally and spatially by X-rays. We review the conceptual development of TNFerade, an adenoviral vector containing radiation-inducible elements of the early growth response-1 promoter upstream of a cDNA encoding human tumor necrosis factor-alpha. We also summarize the preclinical work and clinical trials utilizing this vector as a treatment for diverse solid tumors.

Selective gene expression using a DF3/MUC1 promoter in a human esophageal adenocarcinoma model.

The efficacy of replication-deficient adenoviral vectors in gene therapy is confined to the number of tumor cells the vector infects. To focus and enhance the therapeutic efficacy, we employed a conditionally replication-competent adenoviral vector with a tissue-specific promoter, DF3/MUC1, in a human esophageal adenocarcinoma model. Our results demonstrate that Ad.DF3.E1A.CMV.TNF (Ad.DF3.TNF) specifically replicates in Bic-1 (DF3-producing cells) and mediates an enhanced biologic effect due to increased TNF-alpha in the same DF3-producing cells. We also show that the increased TNF-alpha interacts with ionizing radiation to produce greater tumor regression and a greater delay in tumor regrowth in Bic-1 (DF3-producing cells) compared to Seg-1 (DF3 non-producers). Tumor cell targeting using conditionally replication-competent adenoviral vectors with tumor-specific promoters to drive viral replication and deliver TNF-alpha provides a novel approach to enhancing tumor radiosensitivity.

Complete 5-year follow-up of a prospective phase II trial of preoperative chemoradiotherapy for esophageal cancer.

BACKGROUND: Conclusive evidence supporting the routine use of multimodality therapy in esophageal cancer is lacking. However, since long-term survival after esophagectomy alone is unusual, clinical trials designed to identify effective therapeutic regimens are essential. We report here the 5-year results of a phase II induction chemoradiotherapy trial. METHODS: From August 1991 to January 1995, 44 patients with esophageal or gastroesophageal junction carcinoma were treated with a combination of 5-fluorouracil, cisplatin, and interferon-alpha with concurrent external beam radiotherapy. RESULTS: Forty-one (93%) patients completed chemoradiotherapy, with most toxic events recorded as grade I or II. Curative resection (all gross tumor removed) was achieved in 36 of 37 surgical explorations, with 10 tumors demonstrating complete pathologic response and 23 showing partial pathologic response. Median follow-up for survivors was 75 months (range, 60-100 months). Five-year survival for all patients was 32%, with a median survival of 28 months. Five-year disease-free survival in patients with curative resection was 36% (median, 26 months) and overall survival was 39% (median, 34 months). Five-year survival for patients with curative resection whose disease responded to chemoradiotherapy was 42% (median overall survival, 36 months). Local-regional recurrence alone occurred in 3 patients, distant failure alone in 12 patients, and combined local-regional and distant failure in 2 patients. A Cox proportional hazards model identified both pathologic tumor and nodal stage as independent predictors of disease-free survival. Fourteen patients (32%) were 5-year survivors; 1 of these patients later experienced disease recurrence and died. CONCLUSIONS: Preoperative chemoradiotherapy can result in a long-term and durable disease-free state. Only large, multi-institutional phase III trials can determine whether combined modality therapy is superior to resection alone.

Long-term survival following induction chemoradiotherapy and esophagectomy for esophageal carcinoma.

HYPOTHESIS: Long-term survival is rare in patients treated for esophageal carcinoma. Several clinical trials suggest the possibility of prolonged survival in patients who undergo induction chemoradiotherapy plus esophagectomy. DESIGN: Prospective uncontrolled study. SETTING: University hospital. PATIENTS AND METHODS: Forty-four patients with carcinoma of the esophagus or gastroesophageal junction were prospectively entered into a phase II trial of preoperative 5-fluorouracil, cisplatin, and interferon alfa with concurrent external beam radiotherapy before esophagectomy. Curative resection was performed on 36 of 41 patients who completed the induction chemoradiotherapy. RESULTS: Of the 44 patients, 17 are alive at a median follow-up of 50 months. Of these 17 patients, 15 show no evidence of recurrent disease. Of the 14 patients with long-term survival (> or =3 years), 1 patient died of disease, and another patient is alive with disease. The remaining 12 patients are alive and disease-free (median follow-up, 54 months). Six patients have survived longer than 4 years and 3 patients longer than 5 years. Subsequent primary tumors have developed in 2 patients. One patient had a recurrence at 11 months following initiation of treatment and remains disease-free 43 months postresection of a single brain metastasis. Standard clinicopathologic parameters (age, sex, histologic findings, chemoradiotherapy regimen, and clinical and pathologic stages) were not significantly associated with a survival time of 3 years or longer (Fisher exact test, 2-tailed). Although not significant, p 53 mutational status suggested long-term survival. In 11 of 14 patients who are alive with no history of recurrence, p53 genotyping demonstrated no point mutations in 10 patients. Median survival time for the long-term survivors has not been reached. CONCLUSIONS: Long-term survival can be achieved in patients with esophageal carcinoma who undergo induction chemoradiotherapy and esophagectomy. Recurrence is unlikely in patients who survive for 3 years or longer after undergoing this multimodality treatment.

Is any method of vascular control superior in hepatic resection of metastatic cancers? Longmire clamping, pringle maneuver, and total vascular isolation.

HYPOTHESIS: Although control of the hepatic vascular pedicle is commonly used during hepatic resection, the optimal method of vascular control continues to be debated. The utility of total or selective vascular isolation, pedicle inflow occlusion, or the absence of vascular isolation during minor and major hepatectomy needs to be examined. DESIGN: Retrospective review of hepatic resections performed for either isolated colorectal or noncolorectal hepatic metastases. SETTING: The University of Chicago Hospitals, Chicago, Ill, a tertiary-care referral center. PATIENTS: One hundred forty-one patients who underwent hepatic resection for isolated metastatic liver disease were identified through The University of Chicago Hospitals Tumor Registry. MAIN OUTCOME MEASURES: Intraoperative parameters, perioperative morbidity and mortality, and tumor recurrence. RESULTS: Four groups were compared with alternative methods of vascular management, including total vascular isolation, Longmire clamping, Pringle maneuver, or no vascular control. Tumor number and size were not significantly different between groups. Blood loss and transfusion requirements tended to be higher in the total vascular isolation group and were significantly higher compared with the Pringle group (P =.06) and the no vascular control group (P =.04), but this also correlated with a higher incidence of complexity of surgical resection. The highest incidence of postoperative complications occurred in the total vascular isolation group (P<.05). With similar permanent pathologic margins, the rates of intrahepatic recurrence were similar among all groups, with the no vascular control group having the lowest recurrence rate. CONCLUSIONS: All methods of vascular control appeared equivalent with respect to limiting blood loss and transfusion requirements while providing adequate surgical margins. The highest rates of blood requirements and complications were noted in the total vascular isolation group, which corresponded to the highest incidence of complex resections. The Longmire clamp group incurred the lowest incidence of complications and resulted in identical surgical margins. The application of vascular control is beneficial to surgeons during hepatic resection, but the method of control should be selected based on the location and complexity of resection required and preference of the individual surgeon.

Surgical management of benign tumors of the liver.

INTRODUCTION: Benign tumors of the liver are increasingly being diagnosed and continue to represent a management challenge. These lesions constitute a substantial component of hepatic neoplasms evaluated and resected at a tertiary referral center. We reviewed our experience with resection of benign liver lesions to clarify the safety and effectiveness of this treatment. METHODS: Between January 1996 and January 2000, 28 patients with benign hepatic lesions were identified from a cohort of 140 hepatic resection patients. Demographic characteristics, operative management, morbidity, mortality and follow-up were retrospectively analyzed. RESULTS: The mean age in our patients was 35 +/- 14, with 24/28 (86%) patients being female. Seven of the 24 woman (29%) at presentation were either pregnant or immediate postpartum. A history of OCP use was noted in 14/24 (58%) female patients. The most common presenting symptom was abdominal pain in 12/28 (43%). Resection for an undiagnosed mass occurred in 11/28 (39%) patients. The distribution of pathology was hemangioma 10/28 (35.7%), adenoma 8/28 (28.6%), hepatic cyst 5/28 (17.9%), hamartoma 2/28 (7.1%), and FNH 3/28 (10.7%). Average size of the tumor was 7.4 +/- 3.9 (range 2.5-15 cm) with a mean of 1.4 +/- 0.8 lesions (range 1-3) per patient. Tumors were evenly distributed between the right and left side while eight patients (29%) had bilobar tumors. Enucleation rather than anatomic resection was performed in 18/28 (64%) patients, with a mean blood loss of 457 +/- 532 cc (range 50-2200 cc). Blood transfusion was required in only 3/28 (10%) patients, while total vascular isolation was used in only a single patient undergoing an extended left hepatectomy. Mean length of stay was 6.8 +/- 3.2 d (range 3-14 d). Three complications (10.7%) were encountered: pulmonary embolus, ileus and non-operative bile leak. There were no mortalities in this series. Recurrence of tumor occurred in only one patient with a giant hepatic cyst managed laparoscopically. CONCLUSIONS: In our institution, the management of clinically relevant benign tumors of the liver comprises a significant proportion of our resectional practice (20%). Our data suggests that both enucleation and anatomically based resections can be performed safely with minimal blood loss and transfusion requirements. Resection of symptomatic lesions was highly effective in treating abdominal pain due to these benign tumors. We advocate resection of non-resolving hepatic adenomas, symptomatic lesions, or when malignancy cannot be excluded.

Hepatic resection: effective treatment for primary and secondary tumors.

BACKGROUND: Hepatic resection is an accepted therapeutic modality for isolated colorectal metastases (CRM) and primary hepatobiliary cancers (PC). Controversy continues regarding the safety, efficacy, and appropriateness of resection for noncolorectal metastases (NCM). METHODS: A retrospective review of 167 resections in 160 patients was performed to evaluate the impact of demographics and perioperative data on survival and recurrence. Statistical analyses were performed by Student t test, analysis of variance, and Kaplan-Meier survival estimates. RESULTS: Resections were performed for CRM, 110 of 167 (66%), NCM, 31 of 167 (19%), and PC, 26 of 167 (15%). The interval from primary to metastases was significantly longer in the NCM group than the CRM group (34.7+/-45.1 vs. 18.7+/-23.7 months; P<.01). Mean number of lesions was not different between groups; however, NCM were larger than CRM (5.9+/-4.5 vs 4.5+/-2.9 cm; P<.05). Operative complications were significantly greater for PC (54%) versus CRM and NCM (21% and 19%, respectively; P<.01), although length of stay was similar between groups. Perioperative mortality was 2%. Actuarial survival at 1 year, 3 years, and 5 years was CRM 91%, 54%, and 40%, PC 75%, 60%, and 38%, and NCM 68%, 36%, and not available, respectively (CRM vs. NCM; P<.01 at 3 years). CONCLUSIONS: Hepatic resection for primary and secondary malignancy can be performed with minimal morbidity and mortality. Resection of NCM is associated with a lower overall survival compared with CRM and PC. The disease-free interval from resection of the primary to metastasectomy is prolonged and hepatic recurrence infrequent after resection in the NCM group. These results suggest that tumor biology is a critical determinant of outcome after hepatic resection of primary and secondary hepatic tumors.

Should internal mammary nodes be sampled in the sentinel lymph node era?

BACKGROUND: Controversy exists regarding internal mammary lymph nodes (IMNs) in the staging and treatment of breast cancer. Sentinel lymph node identification with radiocolloid can map drainage to IMNs and directed biopsy can be performed with minimal morbidity. Furthermore, recent studies suggest that IMN drainage of breast tumors may be underestimated. To gain further insight into the prognostic value of IMNs, we reviewed the outcome of patients in whom the IMN status was routinely assessed. METHODS: A retrospective review of 286 patients with breast cancer who underwent IMN dissection between 1956 and 1987 was conducted. RESULTS: Median follow-up is 186 months, age was 52 years (range, 21-85 years), tumor size was 2.5 cm, and number of IMNs removed was 5 (range, 1-22); 44% received chemotherapy, 16% endocrine therapy, and 5% radiotherapy. Presence of IMN metastases correlated with primary tumor size (P < .0001) and number of positive axillary nodes (P < .0001) but did not correlate with primary tumor location or age. Overall, the 20-year disease-free survival is significantly worse for the 25% of patients with IMN metastases (P < .0001). In patients with positive axillary nodes and tumors smaller than 2 cm, there was a significantly worse survival (P < .0001) in the patients with IMN metastases. This difference in survival was not seen in women with tumors larger than 2 cm. CONCLUSIONS: Patients with IMN metastases, regardless of axillary node status, have a highly significant decrease in 20-year disease-free survival. Treatment strategies based on knowledge of sentinel IMN status may lead to improvement in survival, especially for patients with small tumors. At present, sentinel IMN biopsies should be performed in a clinical trial setting.

Initial presentation with stage IV colorectal cancer: how aggressive should we be?

HYPOTHESIS: The appropriate surgical treatment of patients with colorectal cancer who are found on initial presentation to have stage IV disease is controversial. With presumed limited life expectancy, the role of primary colon or rectal resection has been questioned, as has the utility of synchronous hepatic resection. DESIGN: A retrospective chart review. SETTING: The University of Chicago Hospitals, Chicago, Ill, a tertiary-care referral center. PATIENTS: One hundred twenty patients were identified through The University of Chicago Hospitals Tumor Registry whose initial presentation showed stage IV colorectal cancer and who underwent laparotomy. MAIN OUTCOME MEASURES: The primary end points of the study were perioperative morbidity and mortality and overall survival. RESULTS: Median survival and 5-year survival were 14.4 months and 10%, respectively. Survival was greater for patients younger than 65 years than for those who were aged 65 years or older (18.3 vs 9.8 months; P = .007). Carcinomatosis was associated with significantly decreased survival when compared with less extensive stage IV disease (6.7 vs 18.1 months; P<.001). Patients who underwent any form of resection of hepatic metastases achieved a survival advantage over those with unresectable liver lesions (median survival, 29.6 vs 10.2 months; P<.001). Overall, 27 patients (22.5%) developed postoperative complications. Seven patients (5.8%) died during the postoperative period. CONCLUSIONS: Age of 65 years or older, carcinomatosis, and extensive (bilobar) liver involvement are associated with decreased survival and increased postoperative morbidity and mortality and may negate any potential benefit patients derive from resection of the primary lesion. A substantial number of patients with synchronous hepatic metastases have protracted survival that justifies resection of the primary colorectal tumor at initial presentation. Despite the presence of stage IV disease, resection of the primary tumor and, when feasible, liver metastases is indicated.

NM-3, an isocoumarin, increases the antitumor effects of radiotherapy without toxicity.

We examined the effects of a new antiangiogenic isocoumarin, NM-3, as a radiation modifier in vitro and in vivo. The present studies demonstrate that NM-3 is cytotoxic to human umbilical vein endothelial cells (HUVECs) but not to Lewis lung carcinoma (LLC) cells nor Seg-1, esophageal adenocarcinoma cells, in clonogenic survival assays. When HUVEC cultures are treated with NM-3 combined with ionizing radiation (IR), additive cytotoxicity is observed. In addition, the combination of NM-3 and IR inhibits HUVEC migration to a greater extent than either treatment alone. The effects of treatment with NM-3 and IR were also evaluated in tumor model systems. C57BL/6 female mice bearing LLC tumors were given injections for 4 consecutive days with NM-3 (25 mg/kg/day) and treated with IR (20 Gy) for 2 consecutive days. Combined treatment with NM-3 and IR significantly reduced mean tumor volume compared with either treatment alone. An increase in local tumor control was also observed in LLC tumors in mice receiving NM-3/IR therapy. When athymic nude mice bearing Seg-1 tumor xenografts were treated with NM-3 (100 mg/kg/day for 4 days) and 20 Gy (four 5 Gy fractions), significant tumor regression was observed after combined treatment (NM-3 and IR) compared with IR alone. Importantly, no increase in systemic or local tissue toxicity was observed after combined treatment (NM-3 and IR) when compared with IR alone. The bioavailability and nontoxic profile of NM-3 suggests that the efficacy of this agent should be tested in clinical radiotherapy.

Activated natural killer cell tumor retention and cytokine production in colon tumor using a tissue-isolated model.

BACKGROUND: Adoptively transferred activated natural killer (A-NK) cells are capable of selectively infiltrating solid tumors, but only at low efficiency when administered systemically. It is unclear if human A-NK cells can be retained in tumor tissue and, if so, what is their action. We investigated intratumor A-NK cell retention and in situ cytokine production, using an xenogeneic ex vivo tissue-isolated tumor model, which permits direct intraarterial infusion. MATERIALS AND METHODS: Human colon adenocarcinoma (HT-29) was implanted in the ovarian fat pad of nude rats. The tumors were perfused ex vivo 25 to 30 days postimplant with a known number of cells, and the effluent was collected over time. The number of human A-NK cells and cell surface antigen expression of cells infused and exiting the tumor were calculated, using cell counts and flow cytometry, respectively. Frozen sections were stained with Giemsa and also immunostained for the presence of interleukin-2, -4, and -10, tumor necrosis factor alpha (TNF-alpha), and interferon. RESULTS: Six perfusions with 8 x 10(6) A-NK cells were performed. The mean number of infused A-NK cells that remained in the tumor at the completion of perfusion was 4.74 x 10(6) (59.2%). No differences were noted in cellular phenotype between the infused cells and the cells exiting the tumor: expression of the markers CD45 (97.5% vs 94. 5%), CD14 (0 vs 0), CD3 (3.83% vs 2.83%), and CD56 (86% vs 83%) was unchanged, P > 0.05. Microscopic examination of tumor sections showed tumor surrounded by A-NK cells, with some tumor nests infiltrated by A-NK cells. In situ immunopositivity for interleukin-2 (2/6), interleukin-4 (3/6), interleukin-10 (2/6), and TNF-alpha (2/6) specimens was observed. Immunostaining for interferon-gamma was negative. Conclusions. The retention of A-NK cells in the transplanted human colon tumor tissue was found to be efficient (59.2 %) in this model. Although perfusion time was limited, A-NK cells were able to infiltrate the tumor and initiate cytokine production.