Race and ethnicity correlate with survival in patients with gastric adenocarcinoma.

BACKGROUND: Asian centers have consistently reported superior gastric cancer outcomes. Our study examines gastric cancer survival among different races and ethnicities in a large, heterogeneous USA population. PATIENTS AND METHODS: Patients with gastric adenocarcinoma treated in Los Angeles County from 1988 to 2006 were identified from the Los Angeles County Cancer Surveillance Program. Patients were categorized by race and ethnicity as White, Asian, Hispanic and Black. RESULTS: Of 13 084 patients, 39% were White, 22% Asian, 28% Hispanic, 11% Black and 2% other. Asian patients demonstrated higher survival than Whites, Hispanics and Blacks [median survival (MS) 16.3 versus 8.4, 8.7 and 7.9 months, respectively; log-rank P values < 0.001]. Multivariate Cox regression analysis showed that Asians had improved probability of survival [hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.72-0.82; P < 0.001]. In patients who underwent curative-intent surgery, Asian patients demonstrated higher survival than Whites, Hispanics and Blacks (MS 32.7 versus 18.8, 19.9 and 18.9 months, respectively; log-rank P values < 0.001). Multivariate Cox regression analysis showed that Asians had improved probability of survival after surgery (HR 0.79, 95% CI 0.71-0.88; P < 0.001). CONCLUSIONS: Asians with gastric adenocarcinoma have superior outcomes in Los Angeles County. These outcomes verify disparities in gastric cancer survival among different races and ethnicities independent of established clinical and pathologic factors.

In vivo administration of anti-CD3 prevents malignant progressor tumor growth.

Malignant progressor tumors are only weakly immunogenic and can evade host recognition and rejection. One approach to therapy involves activation of the host antitumor cellular effector mechanisms. Since monoclonal antibodies to CD3 (anti-CD3) can activate T cells in vitro, an attempt was made to determine if tumor immunity could be achieved by the administration of anti-CD3 in vivo. T lymphocytes from mice injected with anti-CD3 showed increased interleukin-2 receptor (IL-2R) expression, increased proliferation to recombinant IL-2 (rIL-2), and enhanced reactivity in both an allogeneic mixed lymphocyte reaction and a mixed lymphocyte tumor culture. Malignant tumor growth in treated mice was also examined. The anti-CD3 treatment prevented tumor outgrowth that would have killed untreated animals and also stimulated an in vivo response against a malignant progressor tumor providing lasting tumor immunity.

Robotic-assisted laparoscopic low anterior resection with total mesorectal excision for rectal cancer.

BACKGROUND: With advanced stereoscopic vision, lack of tremor, and the ability to rotate the instruments surgeons find that robotic systems are ideal laparoscopic tools. Because of its high operating cost, however, robotic surgery should be reserved to procedures in which the technology can be of maximum benefit, usually when precise dissections in confined spaces are required. Because conventional laparoscopic total mesorectal excision is a challenging procedure, we have sought to assess the utility of the DaVinci robotic system in laparoscopic low anterior resections for cancer of the rectum. METHODS: Between November 2004 and May 2005 robotic-assisted low anterior resection with total mesorectal excision was performed on six consecutive patients with rectal cancer. These cases were compared with six consecutive low anterior resections performed with conventional laparoscopic techniques by the same surgeon. RESULTS: There were no conversions in either group. Operative and pathological data, complications, and hospital stay were similar in the two groups. Robotic operations appeared to cause less strain for the surgeon. CONCLUSIONS: Robotic-assisted laparoscopic low anterior resection for rectal cancer is feasible in experienced hands. This technique may facilitate minimally invasive radical rectal surgery.

Targeting of human p53-overexpressing tumor cells by an HLA A*0201-restricted murine T-cell receptor expressed in Jurkat T cells.

A potent anti-human (hu) p53 CD8+ CTL response develops in HLA A*0201 transgenic (Tg) mice after immunization with peptides corresponding to HLA A*0201 motifs from hu p53. Mice immunized with the hu P53(149-157) peptide develop a CTL response that is of moderately high affinity and is capable of recognizing hu tumor cells expressing mutated p53. In this report, the mRNAs encoding the predominantly expressed T-cell receptor (TCR) sequences were molecularly cloned from a murine (mu) CTL clone derived from immunized Tg mice, which recognized endogenously processed hu p53 restricted by HLA A*0201. The separate A and B chain TCR cDNAs were transfected in the corresponding TCR A- and B- Jurkat-CD3- mutant T-cell lines, and each rescued CD3 surface expression. Both TCR chains were simultaneously introduced into Jurkat-CD3+ cells, and the transfected Jurkat cells recognized hu T2 cells sensitized with the p53(149-157) CTL epitope but not T2 cells sensitized with a nonspecific CTL epitope. Breast, pancreatic, and sarcoma tumor cell lines, which overexpress endogenous mutated p53, were recognized in the presence of anti-CD28 costimulation, only if they also expressed HLA A*0201. Normal hu fibroblasts established from skin cultures were not recognized. These results represent the first time that a p53-specific TCR capable of recognizing hu cancer cells was heterologously expressed in a naive recipient cell, converting that cell to one recognizing hu tumor cells with mutated p53. This TCR represents a candidate molecule for a genetic strategy in combating hu cancer by an adoptive immunotherapy approach, which uses the strong xenorecognition of hu p53 in mice.

Targeting p53 for adoptive T-cell immunotherapy.

p53 gene mutations occur in most human cancers and result in an altered protein product that accumulates within the cell. Although the observed endogenous human CTL response to p53 is weak, high-affinity, human p53-specific CTLs have been generated from HLA A2.1 transgenic mice immunized with human CTL epitope peptides. In this study, we examine the ability of HLA A2.1-restricted and human p53-specific CTLs from HLA A2.1 transgenic mice to suppress the growth of p53-overexpressing human tumors in severe combined immunodeficient (SCID) mice. In vitro, murine p53(149-157)-specific CTLs selectively lysed the p53-overexpressing pancreatic carcinoma cell line Panc-1 but did not recognize HLA A2.1- tumor cells or HLA A2.1+ normal human fibroblasts. Furthermore, in vivo, the growth of established human tumor xenografts in SCID mice was significantly reduced and survival was prolonged after the administration of p53-specific CTLs but not after the administration of control CTLs or PBS alone. Following treatment with p53(149-157)-specific CTLs, regressing Panc-1 tumors were infiltrated by the CD8+ CTLs, as demonstrated by immunohistochemistry. These findings suggest that p53(149-157)-specific and HLA A2.1-restricted murine CTLs suppress the growth of established Panc-1 tumors following adoptive transfer into SCID hosts and prolong their survival.

Activation of human T cells in vivo following treatment of transplant recipients with OKT3.

Sequential lymph node biopsies were obtained prior to and following OKT3 administration in 10 organ transplant recipients to determine whether activation of human T cells occurs in vivo during OKT3 administration. Within 2 hr after injection, OKT3 can be detected coating LN T cells, and LN T cells also demonstrate enhanced proliferation in vitro in the presence of recombinant interleukin-2 (rIL-2). Interleukin-2 receptor (IL-2R) is expressed on post-OKT3 LN T cells within 48 hr following administration of OKT3. In addition, when placed in a mixed lymphocyte reaction, post-OKT3 LN cells also demonstrate enhanced proliferation. This is the first direct demonstration of in vivo activation of human T cells by OKT3. These data support the hypothesis that T lymphocyte activation and concomitant production of lymphokines are responsible for the side effects associated with OKT3 treatment. Immune activation and possible enhancement of anti-donor MHC alloreactivity may have significant implications for anti-CD3 and anti-TCR monoclonal antibody therapy in clinical organ transplantation and for enhancement of the immune response in cancer patients.

Immunopotentiation of anti-viral and anti-tumor immune responses using anti-T cell receptor antibodies and mitogens.

Although the immunosuppressive properties of anti-CD3 mAbs are now widely recognized, we have accumulated data characterizing the T cell activating properties of these antibodies. While in some situations these activating properties may be viewed as unwanted side-effects (for instance OKT3-mediated T cell activation may be responsible for some of the first dose toxicity seen with patients receiving OKT3 for suppression of allograft rejection), we have shown that anti-CD3 mAb therapy can augment host immune responses and provide protection against some tumors and viral infections. Importantly, this augmented response allows the development of long term, specific immunity. Because the immunosuppressive and activating properties of anti-CD3 mAbs are so closely overlapping, we have sought to identify other agents that are capable of activating T cell subsets selectively. We have found that SEB activates T cell subsets selectively in vivo and that this activation can be exploited to prevent the outgrowth of a malignant murine tumor. Studies currently in progress, including phenotypic and functional analysis of TILs and in vivo T cell subset depletions, should result in a more precise understanding of how SEB-induced T cell activation inhibits tumor growth.

Impact of therapeutic regional lymph node dissection for medullary carcinoma of the thyroid gland.

BACKGROUND: Medullary carcinoma of the thyroid gland (MCT) is a disease commonly associated with regional metastases. Apart from surgical resection, there are limited therapeutic options for such patients. Given the variable and often prolonged survival of such patients, the benefit of surgical resection is difficult to evaluate. We have reviewed our experience with regional lymph node dissection for metastatic MCT. METHODS: From Jan. 1, 1980, to Dec. 31, 1991, 36 patients underwent dissection of regional lymph node metastases for MCT at our institution. Survival was calculated by the Kaplan-Meier method and comparisons by log rank analysis. Significance was defined as p < 0.05. RESULTS: Thirty-six patients (13 women), with a mean age of 48 years (range 16 to 78 years), underwent operation for clinically palpable or radiologically identified nodal disease. Median follow-up was 53 months, with an overall actuarial 5-year survival of 65%. Factors significantly associated with a poor outcome included the following: age greater than 40 years, mediastinal metastases, incomplete excision, extranodal disease, and failure to reduce the thyrocalcitonin level. CONCLUSIONS: The resection of metastatic MCT to regional lymph nodes can be associated with appreciable survival. Prognostic parameters are identified that adversely affect survival.

An orthotopic in vivo model of human pancreatic cancer.

BACKGROUND: Pancreatic cancer is a highly lethal disease that frequently presents in advanced stages. For most patients, treatment with great clinical efficacy does not exist. Relevant in vivo models to test novel therapies are highly desirable. METHODS: The human pancreatic ductal adenocarcinoma cell line Panc-1 was injected intraperitoneally into SCID mice. The pattern of the resulting peripancreatic as well as metastatic disease was examined. Survival experiments after chemotherapy with gemcitabine or doxorubicin, and after immunotherapy with p53-specific cytotoxic T lymphocytes were performed. RESULTS: All animals developed isolated pancreatic tumor implants within 48 hours after injection. After the formation of invasive pancreatic tumor nodules, peripancreatic and portal adenopathy developed, causing biliary obstruction. All tumor-bearing animals died of disease within 5 to 12 weeks. Survival after gemcitabine treatment and after p53-CTL injection was significantly prolonged, with some animals remaining tumor-free. Doxorubicin treatment did not yield extended survival, but led to significant toxicity. CONCLUSION: Intraperitoneal injection of Panc-1 cells into SCID mice produces a quasi-orthotopic tumor development model that shares many characteristics with human pancreatic cancer. The ease of cell injection, avoidance of cumbersome surgical intervention with its resulting mortality, and the reliable development of obstructive jaundice as a dependent comorbid factor render this a useful model for in vivo testing of novel therapeutic approaches to pancreatic cancer. Our initial therapeutic studies demonstrate that in vitro antitumor efficacy against Panc-1 cancer cells does not necessarily predict the in vivo response, highlighting the preclinical experimental value of this model.

Esthetic reconstruction after mastectomy for inflammatory breast cancer: is it worthwhile?

BACKGROUND: Because inflammatory breast cancer (IBC) has been viewed as a malignancy with a poor likelihood of longterm survival, few women have been offered esthetic reconstruction after mastectomy for IBC. Recent advances in multimodality therapy have improved the outcomes for women with this disease. The purpose of this review was to assess the results of esthetic breast reconstruction in the population with IBC. STUDY DESIGN: Review of medical records at the City of Hope National Medical Center for the 10-year period ending in May 1997, revealed 23 women who underwent elective esthetic breast reconstruction after mastectomy for IBC. The records of these patients were reviewed retrospectively. Patients requiring reconstruction for large surgical chest wall defects were not included in the review. RESULTS: Treatment for IBC included mastectomy in all patients, chemotherapy in 22, and chest wall radiation therapy in 14. Immediate reconstruction was performed at the time of mastectomy (n = 14) or was delayed (n = 9). The types of reconstruction included transverse rectus abdominis musculocutaneous flap (n = 18), latissimus dorsi flap (n = 2), or prosthetic mammary implant reconstruction (n = 3). Seven women chose to undergo additional reconstruction procedures (ie, nipple reconstruction) after their initial reconstruction. With a median followup of 44 months for survivors, 16 patients developed recurrence after reconstruction. Of these, 6 were local recurrences and 10 were distant failures. Seven patients are currently alive with no evidence of disease, 4 are currently alive with disease, and 12 have died as a result of breast cancer. The median disease-free survival after reconstruction was 19 months. The median overall survival after reconstruction for all patients was 22 months. The only negative predictor of survival was a positive surgical margin at mastectomy. CONCLUSIONS: The significant emotional and esthetic benefits of breast reconstruction should be available to women with IBC. In light of the improving prognosis of IBC with current aggressive multimodality treatment, reconstructive procedures should be offered as part of comprehensive therapy.

Contralateral prophylactic mastectomy improves the outcome of selected patients undergoing mastectomy for breast cancer.

BACKGROUND: Risk factors for contralateral breast cancer (CBC) may indicate a benefit for contralateral prophylactic mastectomy (CPM) at the time of unilateral mastectomy for breast cancer. The purpose of this study is to evaluate the efficacy of CPM in preventing CBC. METHODS: sixty-four patients undergoing CPM and a control group of 182 patients not undergoing CPM and matched for age, stage, surgery, chemotherapy, and hormonal therapy were retrospectively compared for CBC rate, disease-free survival, and overall survival. RESULTS: Thirty-six CBCs occurred in the control group. In the CPM group, 3 CBCs were found at the time of prophylactic mastectomy, but none occurred subsequently (P = 0.005). Disease-free survival at 15 years in the CPM group was 55% (95% confidence interval [CI] 38% to 69%) versus 28% (95% CI 19% to 36%) in the control group (P = 0.01). Overall survival at 15 years was 64% (95% CI 45% to 78%) CPM versus 48% (95% CI 39% to 58%) in controls (P = 0.26). CONCLUSION: CPM prevented CBC and significantly prolonged disease-free survival. Future studies will need to address risk assessment and contralateral breast cancer prevention in patients treated for early breast cancer.

Transanal excision for low rectal cancers is curative in early-stage disease with favorable histology.

Controversy still exists as to the optimal treatment of early-stage low rectal cancers. Standard resections such as abdominal perineal resections or low anterior resection with coloanal anastomosis can be associated with significant morbidity. Local excision has been considered as a potentially far less morbid option for these patients. We identified 20 patients from our prospective tumor registry database that underwent transanal resection of early rectal cancers between 1988 and 1998. Five patients had carcinoma in situ, and 15 patients had T1 lesions. All T1 lesions were well or moderately well differentiated, and none had lymphovascular invasion. The mean tumor size was 2.65 cm, and the average distance from the anal verge was 4.55 cm. One patient required temporary colostomy because of postoperative complications. Four patients had postoperative adjuvant therapy (radiation alone, two; radiation and chemotherapy, two) for close margins after they refused an abdominal perineal resection. With a median follow-up of 60 months there were no recurrences and no cancer-related deaths. This series suggests that transanal excision is a safe and effective treatment for selected early low rectal cancers with favorable histology.

A mortality-free decade of pancreatoduodenectomy: is quality independent of quantity?

Pancreatoduodenectomy (PD) for periampullary cancer is a procedure of high morbidity and poor long-term survival. Superior clinical outcome has been described in high-volume institutions or for surgeons with a high case load. All patients undergoing pancreatectomy at the City of Hope National Medical Center (Duarte, CA) between 1987 and 1998 were analyzed retrospectively for postoperative outcome, and correlating or predictive clinicopathological factors were identified. Fifty-four patients underwent pancreatectomy [PD, n = 43; pylorus-preserving PD, n = 8; total pancreatectomy, n = 3]. There were 26 males and 28 females, with a median age of 63 years (range, 19-86). Fifty patients had a malignant diagnosis, and four patients had a benign diagnosis. Nine surgical oncologists performed an average of six pancreatectomies (range, 2-8). There was no perioperative death. Postoperative complications occurred in 30 patients, and infections predominated (n = 17). The median hospital stay was 16.5 days. The median postoperative actuarial survival by cancer site was 56 months (ampullary/ bile duct), 32.5 months (duodenal), 22.5 months (pancreatic), and 23.2 months (others). In this 11-year single institutional experience, PD and total pancreatectomy have been performed without lethal complication. In the setting of an exclusive oncology practice, operative mortality rates and survival outcome can be generated that compare favorably to large center experiences. Quality of outcome after pancreatectomy can be independent of quantity.

Asymptomatic renal neoplasms in the rectal cancer patient.

Although cancers of the rectum and kidney are common malignancies the incidence of coexistent rectal and renal primary tumors is unclear. Our objective was to determine the true incidence of synchronous neoplasms of the rectum and kidney. The computed tumor registry database at the City of Hope National Medical Center was queried for patients with synchronous rectal cancer and renal neoplasms presenting between August 1990 and August 2000. During the 10-year period there were 182 patients presenting for treatment of rectal carcinoma. Of these seven (3.8%) were found to have an asymptomatic renal neoplasm. Four patients underwent synchronous resection. Three patients underwent staged renal and rectal resections. The pathology of the renal lesions included renal cell carcinoma in six and an oncocytoma in one patient. Rectal lesions were all adenocarcinomas and all were within 10 cm of the dentate line. Three patients required abdominoperineal resections and four were treated with low anterior resections. Two patients presented with hepatic metastasis at the time of diagnosis. Five patients remain free of disease. Two patients died of persistent and recurrent disease 6 months and 40 months after operation. With the exception of one patient who required prolonged intubation because of severe Parkinson's disease there were no major complications after simultaneous resection of both renal and rectal disease. Simultaneous asymptomatic renal neoplasms may be found in up to 3.8 per cent of patients with rectal cancer. Synchronous lesions may be treated simultaneously without significant morbidity.

Salvage abdominoperineal resection following combined chemotherapy and radiotherapy for epidermoid carcinoma of the anus.

BACKGROUND: Up to one-third of patients with anal epidermoid cancer will fail initial chemoradiotherapy (CT-RT) or have local recurrence after treatment. This study evaluates the Memorial Sloan-Kettering Cancer Center (MSKCC) experience with salvage abdominoperineal resection (APR) in these patients. METHODS: Thirty-eight patients who underwent salvage APR following 5-fluorouracil (5-FU), mitomycin C, and radiotherapy over the past 12 years were analyzed by retrospective review. Survival was calculated by the Kaplan-Meier method and comparisons by log-rank analysis. RESULTS: The indications for APR were recurrent disease after CT-RT in 14 patients and persistent disease in 24 patients. Median follow-up time and survival were 47 and 41 months, respectively. The actuarial 5-year survival was 44%. Twenty-three patients had recurrent disease after APR. Inguinal lymphadenopathy at initial presentation (p < 0.05), fixation of tumor to the pelvic sidewall (p < 0.01), and pathologic involvement of the perirectal fat (p < 0.01) adversely affected survival. Age, gender, initial response to CT-RT, initial stage of the primary tumor, histologic levator muscle involvement, status of perirectal lymph nodes, and extent of lymphadenectomy did not affect survival. CONCLUSIONS: Salvage APR can be expected to yield a moderate number of long-term survivors, but the high rate of disseminated failure suggests the need for additional postoperative treatment.

In vivo administration of anti-CD3 monoclonal antibody can activate immune responses thus preventing malignant tumor growth.

Anti-CD3 monoclonal antibodies (mAb) have been shown to suppress T cell-mediated immune responses both in vitro and in vivo. However, in vitro studies with these antibodies have also demonstrated that they possess potent mitogenic properties, raising the possibility that they might be capable of potentiating immune responses in vivo. In this regard, we have recently shown that an anti-CD3 mAb can activate murine T cells in vivo. Furthermore, low doses of antibody induce interleukin 2 (IL-2) receptor expression and enhanced proliferation to allogeneic major histocompatibility complex (MHC) antigen without detectable modulation or blocking of the T cell receptor and without suppression of T cell-mediated immune responses. In light of these findings, we investigated the ability of low dose anti-CD3 to enhance an anti-tumor response directed against the malignant murine UV-induced skin tumor, 1591-Pro-4L. Low dose anti-CD3 administration resulted in enhanced in vitro anti-tumor activity and prevented tumor outgrowth in approximately two-thirds of animals treated at the time of tumor inoculation. Furthermore, these animals displayed lasting tumor-specific immunity. These results suggest that anti-CD3 mAb can be utilized for the enhancement of anti-tumor responses in vivo and may have general application in the treatment of immunodeficiency.

Exposure of the mucosa of the gastroesophageal junction in patients with Mallory-Weiss tears.

A technique helpful in exposing the mucosal aspect of the gastroesophageal junction is described.

Mechanism of tumor rejection in anti-CD3 monoclonal antibody-treated mice.

The present study was undertaken to determine the mechanism of tumor rejection in mice treated with low dose anti-CD3 mAb. It was found that treated mice developed nonrestricted antitumor cytolytic spleen cells of the Thy-1+, asialo GM-1+, CD4-, CD8- phenotype. Although these cells might play a role in immunopotentiating some immune responses, in vivo depletion studies using anti-asialo GM-1 mAb demonstrated that these cells were not involved in the rejection of the progressor tumor, 1591-PRO4L, by anti-CD3 mAb-treated mice. Mice treated with anti-CD3 did develop lasting tumor specific immunity as demonstrated by their ability to reject PRO4L on tumor rechallenge while being unable to reject an unrelated UV-induced tumor. The specificity of this memory implicated T cells in the response to PRO4L in anti-CD3-treated mice. Using in vivo T cell subset depletion of anti-CD3-treated animals, it was shown that both CD4+ and CD8+ T cells are required for anti-CD3-induced tumor rejection. The CD4+ cells provide helper function and are only required in the early rejection period, whereas CD8+ cells are required throughout the immune response. In fact, examination of rejecting tumors from treated animals revealed the presence of tumor-specific CD8+ cytolytic T cells capable of cytolysis immediately after removal from the rejecting PRO4L tumor. Thus, in vivo treatment with anti-CD3 mAb likely results in the pan-stimulation of the entire T cell population, which enhances the generation of specific CD8+ T cells, which then eliminate the tumor.