Improved Survival with Anti-VEGF Therapy in the Treatment of Unresectable Appendiceal Epithelial Neoplasms.

BACKGROUND: Currently, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are accepted treatments for surgically resectable appendiceal epithelial neoplasms. However, for nonsurgical candidates, systemic treatment may be considered. The purpose of this analysis was to determine the benefit of biologic therapy (anti-vascular endothelial growth factor and anti-epidermal growth factor receptor) in addition to systemic chemotherapy in this select patient population. METHODS: The MD Anderson Cancer Center tumor registry was retrospectively reviewed for systemic treatment-naive appendiceal epithelial neoplasm patients registered between January 2000 to July 2007 for prior cytoreductive surgery and hyperthermic intraperitoneal chemotherapy status, histologic grade, signet ring pathology, systemic chemotherapy, biologic therapy, tumor markers (carcinoembryonic antigen, carbohydrate antigen [CA] 125, and/or CA19-9), progression-free survival (PFS), overall survival (OS), and disease control rate. Kaplan-Meier method, log-rank, and Cox proportional hazard regression models were used for statistical analysis. RESULTS: A total of 353 patients were identified; 130 patients met the inclusion criteria. Fifty-nine patients received biologic therapy. The use of the anti-vascular endothelial growth factor (VEGF) agent bevacizumab improved both OS (42 months vs. 76 months, hazard ratio 0.49 [95 % confidence interval 0.25-0.94] P = 0.03) and PFS (4 months vs. 9 months, hazard ratio 0.69 [95 % confidence interval 0.47-0.995], P = 0.047) for all histologic subtypes. Moderately differentiated tumors had an improved PFS relative to well-differentiated tumors, 9 months versus 3 months (P = 0.05). CONCLUSIONS: Bevacizumab in combination with chemotherapy appears to play a role in surgically unresectable appendiceal epithelial neoplasm patients, with an improvement in PFS and OS. Anti-VEGF agents should be strongly considered in the management of patients with higher-grade appendiceal epithelial neoplasms who are suboptimal candidates for surgical resection.

Is surviving enough? Coping and impact on activities of daily living among melanoma patients with lymphoedema.

We assessed the impact of lymphoedema (defined as ≥ 10% limb volume change) on quality of life (QOL), ability to perform activities of daily living (ADLs) and coping in 277 melanoma patients. Limb volume was measured prospectively, pre-operatively and every 3-6 months for 18 months post-operatively using a perometer. Three questionnaires were administered to measure QOL, coping and impact on ADLs. Statistical analyses were conducted using longitudinal logistic regression models. At 18 months, the cumulative incidence of lymphoedema was 31% in patients with upper extremity nodal basin treatment and 40% in lower extremity nodal basin treatment patients. Patients with lower extremity lymphoedema reported lower QOL scores than those with upper extremity lymphoedema. Over 18 months, both groups with mild and moderate lymphoedema showed improvement in coping [odds ratio (OR): 6.67, 95% confidence interval (CI): 3.30-13.47] and performance of ADLs (OR: 7.46, CI: 3.38-16.47). Over the course of 18 months, men were found to have poorer coping scores than women (OR: 2.91, CI: 1.35-6.27). Lymphoedema was associated with improvement in coping over time (P = 0.08) and a higher reported interference with ADLs (OR: 2.53, CI: 1.29-4.97). Patient education about lymphoedema at the time of surgical consent may improve self-efficacy and coping ability. Effective management of lymphoedema may improve patient QOL and reduce interference with ADLs.

A T cell-independent antitumor response in mice with bone marrow cells retrovirally transduced with an antibody/Fc-gamma chain chimeric receptor gene recognizing a human ovarian cancer antigen.

In order to treat common cancers with immunotherapy, chimeric receptors have been developed that combine the tumor specificity of antibodies with T-cell effector functions. Previously, we demonstrated that T cells transduced with a chimeric receptor gene against human ovarian cancer were able to recognize ovarian cancer cells in vitro and in vivo. We now report that recipients of bone marrow cells transduced with these genes exhibited significant antitumor activity in vivo. Moreover, in vivo depletion of T cells in reconstituted mice did not affect antitumor activity, suggesting that other immune cells expressing the chimeric receptor gene may play an important role in tumor rejection.

Dendritic cells retrovirally transduced with a model antigen gene are therapeutically effective against established pulmonary metastases.

Dendritic cells (DCs) are bone marrow-derived leukocytes that function as potent antigen presenting cells capable of initiating T cell-dependent responses from quiescent lymphocytes. DC pulsed with tumor-associated antigen (TAA) peptide or protein have recently been demonstrated to elicit antigen-specific protective antitumor immunity in a number of murine models. Transduction of DCs with TAA genes may allow stable, prolonged antigen expression as well as the potential for presentation of multiple, or unidentified, epitopes in association with major histocompatibility complex class I and/or class II molecules. To evaluate the potential efficacy of retrovirally transduced DCs, bone marrow cells harvested from BALB/c mice were transduced with either a model antigen gene encoding beta-galactosidase (beta-gal) or a control gene encoding rat HER-2/neu (Neu) by coculture with irradiated ecotropic retroviral producer lines. Bone marrow cells were differentiated into DC in vitro using granulocyte/macrophage colony-stimulating factor and interleukin-4. After 7 d in culture, cells were 45-78% double positive for DC phenotypic cell surface markers by FACS(R) analysis, and DC transduced with beta-gal were 41-72% positive for beta-gal expression by X-gal staining. In addition, coculture of beta-gal transduced DC with a beta-gal-specific T cell line (CTLx) resulted in the production of large amounts of interferon-gamma, demonstrating that transduced DCs could process and present endogenously expressed beta-gal. DC transduced with beta-gal and control rat HER-2/neu were then used to treat 3-d lung metastases in mice bearing an experimental murine tumor CT26.CL25, expressing the model antigen, beta-gal. Treatment with beta-gal-transduced DC significantly reduced the number of pulmonary metastatic nodules compared with treatment with Hank's balanced salt solution or DCs transduced with rat HER-2/neu. In addition, immunization with beta-gal-transduced DCs resulted in the generation of antigen-specific cytotoxic T lymphocytes (CTLs), which were significantly more reactive against relevant tumor targets than CTLs generated from mice immunized with DCs pulsed with the Ld-restricted beta-gal peptide. The results observed in this rapidly lethal tumor model suggest that DCs transduced with TAA may be a useful treatment modality in tumor immunotherapy.

Retroviral transduction of human dendritic cells with a tumor-associated antigen gene.

Dendritic cells (DCs) are potent antigen-presenting cells that can activate quiescent T lymphocytes. When pulsed with tumor-associated antigen (TAA) peptide or protein, murine DCs can provide antitumor immunity. We reasoned that DCs retrovirally transduced with TAA genes might have important advantages over peptide- or protein-pulsed DCs, including long-term TAA presentation in vivo, and presentation of important but undefined epitopes. Therefore, we attempted to retrovirally transduce human DCs with a melanoma TAA gene (MART-1) and determine whether these transduced DCs could raise a specific antitumor response from quiescent autologous T lymphocytes. After retroviral transduction, human CD34+ cells were differentiated into DCs in vitro using granulocyte macrophage colony-stimulating factor, tumor necrosis factor alpha, and stem cell factor. This method consistently yielded a population of DCs as analyzed by morphology, phenotype, and MLR. Flow cytometric analysis revealed that 22-28% of cells expressing the DC phenotype also expressed a transduced marker gene. When DCs were transduced with the gene encoding MART-1, they stimulated much higher levels of cytokine release by MART-1-specific tumor-infiltrating lymphocytes than control DCs transduced with an irrelevant gene. In vitro stimulation using MART-1-transduced DCs but not control-transduced DCs raised specific antitumor CTLs from autologous quiescent T cells. These results provide evidence that human DCs can be retrovirally transduced with a TAA gene and that these transduced cells can raise a specific antitumor immune response in vitro. Transduced DCs may be useful for in vivo immunization against TAA.

Recognition of human colon cancer by T cells transduced with a chimeric receptor gene.

Transduction with chimeric T-cell receptor genes can be used to redirect primary T lymphocytes to recognize specific antigens (Ags), including ovarian and breast cancer Ags. To extend this approach to colon cancer we report here redirection of T cells using a chimeric receptor recognizing the colon cancer-associated Ag EGP40. Chimeric T cell receptors were constructed by ligating single-chain genes of either of two EGP40-specific monoclonal antibodies (CO17.1 A, GA733) to the Fc receptor gamma-signaling chain. Retroviral vectors incorporating these constructs were used to transduce a murine T-cell line and human peripheral blood lymphocytes. These modified T cells were analyzed for specific recognition of colon cancer lines by measuring cytokine release and lytic activity against tumor targets. Murine lymphocytes transduced with the chimeric receptor based on GA733, but not CO17.1A, released cytokine specifically in response to EGP40-expressing colon cancer cell lines. Recognition of colon cancer targets by murine lymphocytes was blocked by the addition of GA733 antibody or soluble EGP40 Ag, confirming that colon cancer recognition is based on specific chimeric receptor-Ag interaction. Human lymphocytes transduced with chimeric GA733 specifically recognized colon carcinoma cells in cytokine release assays and lysed EGP40-expressing tumor cells. Genetic modification of T cells can be used to redirect T cells against EGP40-expressing tumor cells. The expression of chimeric GA733 in the autologous lymphocytes of patients may provide a source of tumor-reactive cells with therapeutic application against colon cancer.

Advanced proximal colon cancer.

BACKGROUND: Two recent studies have documented that sigmoidoscopy as a screening tool for colorectal cancers may miss advanced proximal colonic neoplasms. The purpose of this study was to assess the prevalence of distal synchronous lesions in patients with proximal colon cancer. We sought to determine if screening sigmoidoscopy would have missed these proximal colon cancers. METHODS: Data were collected on all patients (n = 305) diagnosed with colorectal cancer over a 6-year period. Patients were stratified by age, sex, tumor location, presenting complaint, AJCC stage, and TNM classification. The colonoscopy results of patients diagnosed with proximal colon cancer were analyzed to determine the incidence of synchronous distal colon lesions. RESULTS: Proximal colon cancer was diagnosed in 88 patients (29%). Of those studied, 45 (54%) did not have synchronous distal lesions detected by colonoscopy. The patients with proximal colon cancer were elderly (mean age 67), had advanced tumor size [59 patients (67%) T3/T4], and had advanced AJCC stages [37 patients (42%) stage III/IV]. Nearly all patients [84 (95%)] with proximal colon cancer were symptomatic. CONCLUSION: In this study, the majority of patients with proximal colon cancer did not have a synchronous lesion in the distal colon. Current screening methods for colon cancer based on sigmoidoscopy would not have identified these proximal lesions. These findings support the incorporation of screening colonoscopy in protocols designed to identify early colon cancer.

Luminal narrowing after autoanastomosis and intraluminal slough in intussusception: a case report and historical review.

Historical literature notes slough of an intussusceptum with autoanastomosis as an infrequent natural course of childhood intussusception resulting in survival. The case of an 8-year-old boy with abdominal pain several years after an apparent untreated childhood intussusception is presented. Cecal resection shows evidence of previously sloughed intussusceptum with cicatral luminal narrowing at site of autoanastomosis. This case illustrates a rare cause of abdominal pain and partial intestinal obstruction in childhood.

Repair of mucosal perforation during pyloromyotomy: surgeon's choice.

Mucosal perforation during Fredet-Ramstedt pyloromyotomy traditionally has been repaired with muscular and mucosal reapproximation, pyloric rotation, and repeat myotomy. The purpose of this study was to determine whether simple mucosal closure is a safe alternative repair technique for such a perforation. The authors reviewed their experience of pyloromyotomies over a 21-year period and found a 1.67% incidence (15 of 896) of mucosal perforation. Four of these patients had repair with rotation and repeat myotomy, and 11 had repair with primary mucosal approximation. The patients were compared with respect to demographics, duration of operation, postoperative feeding intolerance, time from operation until discharge, and postoperative complications. No differences were noted between the two groups. Interestingly, when the perforation group (n = 15) was compared with the nonperforation group (n = 881), the mean age at time of pyloromyotomy was significantly higher for the group with perforation 48 days v 34 days; P = .0021, Student's t test). The authors conclude that those most likely to suffer mucosal perforation during pyloromyotomy are older patients with pyloric stenosis. Such mucosal perforation can be repaired with equal efficacy and safety using the traditional pyloric rotation approach or primary mucosal closure.

Extended myectomy-myotomy. A therapeutic alternative for total intestinal aganglionosis.

OBJECTIVE: That total intestinal aganglionosis (extended Hirschsprung's disease) is uniformly incompatible with life as reported in 1985, is challenged by this series of patients treated over the last 7 years with an alternative therapy, extended myectomy-myotomy of the small bowel. SUMMARY BACKGROUND DATA: A total of 16 neonates worldwide presented with intestinal obstruction secondary to total (extending to the stomach) or near total (to 40 cm of jejunum) intestinal aganglionosis confirmed at one or more leveling operations. METHODS: A patient questionnaire was answered by the surgeon of all 16 patients. RESULTS: The sex distribution was eight boys and eight girls. The definitive operation included extending an antimesenteric myectomy-myotomy from the ganglionic-aganglionic transition zone for variable lengths, the operative design being to create sufficient small bowel length to support life (40-cm minimum, total small bowel maximum). The myectomized bowel was terminated as an end-stroma or as an isolated jejuno-ileal segment. Ten of 16 patients have survived (62.5%) whose length of ganglionated bowel varies from 0 to 40 cm (mean, 12.4 cm; median, 6.0 cm). Six patients have died from 1 to 33 months after operation (mean, 9.5 months; median, 5.0 months) of gut-induced infection (n = 5) and respiratory failure (n = 1); their ganglionated bowel length was similar to survivors (range, 0-26 cm; mean, 9.2 cm; median, 8.0 cm). Of the 16 patients, 15 have received enteral nutrients through the myectomized bowel. Of ten survivors, strikingly two are totally gut nourished (2 cm, 7-cm length of ganglionated bowel), six receive from 1/5 to 4/5 of total calories enterally, and one receives minimal enteral feeding. CONCLUSIONS: From these patients we have learned that (1) extended myectomy-myotomy relieves the obstruction of extended Hirschsprung's disease; (2) aganglionic bowel after extended myectomy-myotomy acts as a passive conduit for proximally propulsed nutrients; and (3) aganglionic bowel after extended myectomy-myotomy undergoes adaptive change and is capable of absorbing life-supporting nutrients. These data demonstrate extended myectomy-myotomy to be a therapeutic option for otherwise fatal extended Hirschsprung's disease, either as a potentially definitive therapy or as a putative bridge to intestinal transplantation.

Retrovirally transduced human dendritic cells can generate T cells recognizing multiple MHC class I and class II epitopes from the melanoma antigen glycoprotein 100.

Involvement of tumor-Ag specific CD4(+) and CD8(+) T cells could be critical in the generation of an effective immunotherapy for cancer. In an attempt to optimize the T cell response against defined tumor Ags, we previously developed a method allowing transgene expression in human dendritic cells (DCs) using retroviral vectors. One advantage of using gene-modified DCs is the potential ability to generate CD8(+) T cells against multiple class I-restricted epitopes within the Ag, thereby eliciting a broad antitumor immune response. To test this, we generated tumor-reactive CD8(+) T cells with DCs transduced with the melanoma Ag gp100, for which a number of HLA-A2-restricted epitopes have been described. Using gp100-transduced DCs, we were indeed able to raise T cells recognizing three distinct HLA-A2 epitopes within the Ag, gp100(154-162), gp100(209-217), and gp100(280-288). We next tested the ability of transduced DCs to raise class II-restricted CD4(+) T cells. Interestingly, stimulation with gp100-transduced DCs resulted in the generation of CD4(+) T cells specific for a novel HLA-DRbeta1*0701-restricted epitope of gp100. The minimal determinant of this epitope was defined as gp100(174-190) (TGRAMLGTHTMEVTVYH). These observations suggest that retrovirally transduced DCs have the capacity to present multiple MHC class I- and class II-restricted peptides derived from a tumor Ag, thereby eliciting a robust immune response against that Ag.

Increased functional expression of transgene in primary human lymphocytes using retroviral vectors modified with IRES and splicing motifs.

Genetic modification of human lymphocytes is being employed in strategies to correct enzyme deficiencies, encode cytokines and to redirect lymphocytes to antigenic targets other than those encoded by their endogenous T cell receptor. However, expression of transgenes in primary lymphocytes is generally low. Reasoning that vector modification may lead to increased transgene expression and subsequent increases in function, we have performed two retroviral vector modifications and report their effect on the functional expression in primary lymphocytes. A chimeric receptor specific for the colon carcinoma-associated antigen, EGP40, was initially incorporated into the retroviral vector LXSN. In this vector, receptor expression is driven by the Moloney murine leukemia virus LTR, and neomycin phosphotransferase expression driven by the SV40 promoter. Replacement of SV40 with an internal ribosomal entry site (IRES) increased the transgene activity of a mouse T cell line and human PBL as judged by increased cytokine release in response to antigen positive target cells. A further increase in transgene function was generated by the additional incorporation of a splice acceptor motif into the construct. Human PBL transduced with vector incorporating both IRES and intron were consistently more effective at lysing antigen positive colorectal carcinoma cells.

Thyroid dysfunction in 281 patients with metastatic melanoma or renal carcinoma treated with interleukin-2 alone.

The purpose of this prospective study was to determine the incidence of thyroid dysfunction in cancer patients receiving immunotherapy with interleukin-2 (IL-2) alone, and to assess the relationship of hypothyroidism to clinical response. A cohort of 281 consecutive patients with metastatic melanoma or renal carcinoma were treated with IL-2 alone from July 1, 1989 until June 30, 1993. The majority (n = 216) received high-dose IL-2 and the remainder (n = 65) received low-dose therapy. Thyroid function was measured before, during, and after immunotherapy. Forty-one percent of initially euthyroid patients developed thyroid dysfunction after starting high-dose IL-2-alone therapy. The most common abnormality was hypothyroidism, occurring in 35% of patients, although moderate or severe hypothyroidism requiring thyroid hormone replacement occurred in 9% of patients. Hypothyroidism was related to duration of IL-2 therapy and was not associated with clinical response. Hyperthyroidism developed in 7% of previously euthyroid patients receiving high-dose IL-2. Overall, the incidence of thyroid dysfunction was similar in the high- and low-dose IL-2 regimens. In conclusion, thyroid dysfunction is a common sequela of IL-2 therapy. Thyroid function should be measured routinely in cancer patients receiving IL-2-based treatment. It is recommended that thyroid hormone replacement be given to patients with moderate or severe hypothyroidism.

Correlates of response to IL-2 therapy in patients treated for metastatic renal cancer and melanoma.

PURPOSE: We evaluated the characteristics of patients with metastatic renal cancer or metastatic melanoma prior to and during treatment with bolus intravenous interleukin-2 to define prognostic indicators of subsequent response to therapy. PATIENTS AND METHODS: A consecutive series of 509 patients with progressive metastatic cancer were treated with intravenous interleukin-2 from September 1985 to July 1993. Pretreatment demographic characteristics, treatment history, results of laboratory tests, and metastatic sites of disease were evaluated. The amount of interleukin-2 administered, toxicity, and changes in laboratory test results were recorded for the first course of therapy. Subsequent objective response to therapy and survival were determined and used to evaluate pretreatment and treatment characteristics that acted as prognostic indicators of response. RESULTS: At the end of the study, 22.6% of patients with renal cancer and 16.3% of patients with melanoma experienced an objective response to interleukin-2 therapy. Patients with renal cancer responded more frequently if they had not previously failed other immunotherapies. Also, renal cancer patients who achieved an objective response had a more profound thrombocytopenia during the first cycle of therapy. Patients with melanoma responded more frequently to interleukin-2 therapy when metastases were confined to subcutaneous tissue. In addition, responding patients with melanoma received more interleukin-2 in their first course and exhibited a more profound lymphocytosis 7 to 11 days after initiating therapy than did nonresponders. CONCLUSIONS: Renal cancer and melanoma displayed separate prognostic indicators with respect to response from interleukin-2 therapy. Although significant correlates to response were identified, there was much variability and a reliable predictive model of response to therapy could not be formulated based on these results.