Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma.

PURPOSE: The present study attempted to identify characteristics that correlated with clinical response to interleukin (IL)-2 therapy in patients with metastatic melanoma. PATIENTS AND METHODS: We retrospectively evaluated laboratory and clinical characteristics of 374 consecutive patients with metastatic melanoma treated with high-dose intravenous bolus IL-2 (720,000 IU/kg) from July 1, 1988, to December 31, 1999, at the Surgery Branch of the National Cancer Institute. RESULTS: The overall objective response rate was 15.5%. Pretreatment parameters such as patient demographics, laboratory values, and prior therapy did not correlate with response; however, 53.6% of patients with only subcutaneous and/or cutaneous metastases responded, compared with 12.4% of patients with disease at other sites (P2 =.000001). During therapy, patients who were responders tended to have received more doses during course 1 (16.2 +/- 0.3 doses v 14.5 +/- 0.2 doses; P2 =.0095); however, when limited to patients who were able to complete both cycles of course 1, there was no statistically significant difference (P2 =.27). Responders had a higher maximum lymphocyte count immediately after therapy compared with nonresponders (P2 =.0026). The development of abnormal thyroid function tests and vitiligo after therapy was associated with response (thyroid-stimulating hormone, P2 =.01; free T4, P2 =.0049; vitiligo, P2 < 10(-6)), although thyroid dysfunction may have been related more to the length of IL-2 therapy than to response. CONCLUSION: The presence of metastases only to subcutaneous and/or cutaneous sites, lymphocytosis immediately after treatment, and long-term immunologic side effects, especially vitiligo, were associated with antitumor response to IL-2 therapy.

T-cell-directed cancer vaccines: mechanisms of immune escape and immune tolerance.

Recent clinical trials using vaccines directed toward tumour-associated antigens (TA) have shown the increasing capacity of vaccines to cause immunologic responses. In fact, strongly reactive TA-specific cytolytic T-lymphocytes and tumour-infiltrating lymphocytes (TIL) can be identified and expanded ex vivo from patients with metastatic melanoma vaccinated with melanoma-associated antigens. Paradoxically, this strong immunological response does not correlate with clinical tumour regression. Proposed mechanisms responsible for this glaring inconsistency are numerous and varied; systemic immunosuppressive as well as local mechanistic factors are implicated. In this review we will critically evaluate the possible mechanisms that allow tumours to escape immune destruction and be tolerated by the immune system. In addition, strategies that may allow further insight into the biology of tumour rejection are discussed, in the hope of deepening the understanding of this phenomenon and enhancing its therapeutic potential.

T-cell-directed cancer vaccines: the melanoma model.

Significant advances in the understanding of the molecular basis for tumour/host interactions in humans have occurred in the last decade through studying patients with metastatic melanoma. This disease is characterised by its tendency to be modulated by immunologic factors. Furthermore, immunologic manipulation of the host with various systemic agents, in particular IL-2, frequently affects this natural phenomenon and can lead to complete rejection of cancer. By studying the cellular immunology occurring in patients undergoing immunotherapy, several tumour antigens (TA) and their epitopes recognised by human leukocyte antigen (HLA) class I-restricted cytotoxic T-lymphocytes (CTL) have been identified. Most of these TA are non-mutated molecules expressed by the majority of melanoma in vivo and most melanoma cell lines. In addition, unique minimal epitopic sequences play an immunodominant role in the context of specific HLA class I alleles. Since melanoma lesions from different patients often share expression of the same TA, and a minimal peptide sequence from a TA can cause immunologic changes in multiple patients, interest has grown in the development of TA-specific vaccines suitable for broad patient populations. Repeated in vitro stimulation of peripheral blood mononuclear cells (PBMC) with TA-derived epitopes can induce a high frequency of TA-reactive T-cells in melanoma patients. The same epitopes can also enhance TA-specific T-cell reactivity in vivo when administered subcutaneously in combination with Incomplete Freund's Adjuvant (IFA). Epitope-based vaccinations, however, have not shown strong clinical efficacy unless combined with IL-2 administration. Attempts to increase the efficacy of these vaccines have combined specialised antigen-presenting cells or the administration of whole TA through DNA- or RNA-based vaccines with the intention of increasing antigen presentation and processing. Save for scattered reports, however, the success of these approaches has been limited and T-cell-directed vaccination against cancer remains at a paradoxical standstill whereby anticancer immunisation can be induced but it is not sufficient, in most cases, to induce tumour regression. Using melanoma as the standard model for immunotherapy, we will review various methods of T-cell-directed vaccination, the monitoring and analysis of the resulting immune response, and several clinical trials in which cancer vaccines have successfully induced immunisation.

Pancreaticoduodenectomy for selected periampullary neuroendocrine tumors: fifty patients.

BACKGROUND: Most resectable pancreatic or peripancreatic neuroendocrine tumors are treated by enucleation or distal pancreatectomy. A minority of tumors may require pancreaticoduodenectomy for complete tumor excision because of their large size, location, or lymph node involvement. METHODS: This study reviews the management of 50 patients treated by pancreaticoduodenectomy for periampullary neuroendocrine tumors between 1962 and 1996 at a single institution. RESULTS: There were 30 men and 20 women with a mean age of 52 +/- 2 years. Functional tumors were resected in 17 patients: insulinoma, seven tumors; gastrinoma, eight tumors; vipoma, one tumor; and glucagonoma, one tumor. Tumors were classified as malignant in 29 patients and benign in 21. The median intraoperative blood loss was 800 ml, and the median number of units of blood transfused was zero. The postoperative length of stay was 20 +/- 2 days. Postoperative morbidity included 11 patients (24%) with a pancreatic fistula and four patients (8%) with a biliary fistula. There was one in-hospital death (2%), in 1967. The actuarial survival rates at 2, 5, and 7 years are 81%, 73%, and 65%, respectively. Patients with benign tumors had a significantly improved 5-year survival rate (94%) compared with those with malignant tumors (61%; p = 0.03). CONCLUSIONS: Selected patients with periampullary neuroendocrine tumors can be managed successfully by pancreaticoduodenectomy, with low mortality and acceptable morbidity rates.

Intramural esophageal dissection.

A case of intramural esophageal dissection is reported and the literature reviewed. Patients with intramural esophageal dissection are usually women in their seventh or eighth decade. The most common presenting symptoms are chest pain, dysphagia, and hematemesis. The diagnosis is made by contrast esophagography, esophagoscopy, or both. Nonoperative therapy has proved to be uniformly successful.

Surgical experience with pancreatic and peripancreatic neuroendocrine tumors: review of 125 patients.

Neuroendocrine tumors of the pancreas and peripancreatic area are rare entities with a wide spectrum of clinical presentation. This study retrospectively reviews the patients who underwent surgery for these tumors at The Johns Hopkins Hospital from 1949 to 1996, inclusive. There were 125 patients (65 males and 60 females) whose mean age was 51 +/- 1 years. Fifty-eight patients (48%) had nonfunctional tumors, whereas 64 (52%) had functional tumors: 35 (55%) insulinomas, 23 (36%) gastrinomas, three (5%) VIP-omas, two (3%) glucagonomas, and one (1%) ACTHoma. All patients with functional tumors presented with appropriate signs and symptoms of hormonal excess; 86% of patients with nonfunctional tumors presented with weight loss, abdominal pain, or jaundice. Preoperative computed tomography (CT) correctly localized the tumor in 66 (76%) of 87 patients; angiography in 45 (58%) of 78 patients; and CT plus angiography in 54 (79%) of 68 patients. Tumors were benign in 60 patients (48%), malignant in 65 patients (52%), and were located in the head, neck, or uncinate process of the pancreas in 54, body in 14, tail in 18, and duodenum in eight. The most common operative procedures performed were 50 pancreaticoduodenectomies (40%), 39 distal pancreatectomies (31%), and 21 tumor enucleations (17%). Nine synchronous hepatic resections were performed for metastases. Of the evaluable patients, 46 (43%) had postoperative complications, the most common of which were pancreatic fistula (16%), wound infection (15%), and delayed gastric emptying (8%). There were three in-hospital deaths (2.8%). With a mean follow-up of 55 +/- 6 months, there have been 30 additional deaths, 23 of which were related to disease progression. The overall 2-, 5-, and 10-year actuarial survival rates were 82%, 65%, and 47%, respectively. The 5-year survival for patients with functional tumors was 77% compared to 52% for those with nonfunctional tumors (P = 0.025); the 5-year survival for patients with benign tumors was 91% compared to 49% for those with malignant tumors (P=0.0004). By univariate analysis the most powerful predictor of poor outcome for patients with malignant tumors (n = 60) was positive surgical margins (P=0.006). This single-institution experience documents low mortality and moderate morbidity for patients treated operatively for pancreatic and peripancreatic neuroendocrine tumors. The most favorable outcomes are observed in patients with benign functional tumors and in those with completely resected malignant tumors.

Surgical experience with pancreatic and peripancreatic neuroendocrine tumors: Review of 125 patients.

Neuroendocrine tumors of the pancreas and peripancreatic area are rare entities with a wide spectrum of clinical presentation. This study retrospectively reviews the patients who underwent surgery for these tumors at The Johns Hopkins Hospital from 1949 to 1996, inclusive There were 125 patients (65 males and 60 females) whose mean age was 51 +/- 1 years Fifty-eight patients (48%) had nonfunctional tumors, whereas 64 (52%) had functional tumors 35 (55%) insulinomas, 23 (36%) gastrmomas, three (5%) VIP-omas, two (3 %) glucagonomas, and one (1%) ACTHorna All patients with functional tumors presented with appropriate signs and symptoms of hormonal excess, 86% of patients with nonfunctional tumors presented with weight loss, abdominal pain, or jaundice Preoperaüve computed tomography (CT) correctly localized the tumor in 66 (76%) of 87 patients, angiography in 45 (58%) of 78 patients, and CT plus angiography in 54 (79%) of 68 patients Tumors were benign in 60 patients (48%), malignant m 65 patients (52%), and were located in the head, neck, or uncinate process of the pancreas in 54, body in 14, tail in 18, and duodenum in eight The most common operative procedures performed were 50 pancreaacoduodenectomies (40%), 39 distal pancreatectomies (31%), and 21 tumor enucleations (17%) Nine synchronous hepatic resections were performed for métastases Of the evaluable patients, 46 (43%) had postoperative complications, the most common of which were pancreatic fistula (16%), wound infection (15%), and delayed gastric emptying (8%) There were three in-hospital deaths (2 8%) With a mean follow-up of 55 +/-6 months, there have been 30 additional deaths, 23 of which were related to disease progression The overall 2-, 5-, and 10-year actuarial survival rates were 82%, 65%, and 47%, respectively The 5-year survival for patients with functional tumors was 77% compared to 52% for those with nonfunctional tumors (P = 0 025), the 5-year survival for patients with benign tumors was 91% compared to 49% for those with malignant tumors (P = 0 0004) By univanate analysis the most powerful predictor of poor outcome for patients with malignant tumors (n = 60) was positive surgiad margins (P = 0 006) This single-institution experience documents low mortality and moderate morbidity for patients treated operatively for pancreatic and penpancreaac neuroendocrine tumors The most favorable outcomes are observed in patients with benign functional tumors and in those with completely resected malignant tumors.

Laser scanning cytometry evaluation of MART-1, gp100, and HLA-A2 expression in melanoma metastases.

Assessment of antigen expression by solid tumors has relied predominantly on immunohistochemistry, flow cytometry, and more recently quantitative real-time polymerase chain reaction. However, all these techniques present intrinsic limits. The laser scanning cytometer, by combining the properties of light and fluorescence microscopy with those of laser cytometry, can quantitatively and objectively analyze hypocellular samples such as fine-needle aspirates on an individual cell basis. To validate the fidelity of laser scanning cytometry for quantitative immunophenotyping of fine-needle aspirates, the authors measured the expression of the melanoma-associated antigens MART-1 and gp100 as well as HLA-A2, a HLA class 1 restriction element associated with their recognition by melanoma-specific T cells. Expression of melanoma antigens and HLA was measured by laser scanning cytometry and immunohistochemistry in fine-needle aspirates from melanoma metastases. In addition, transcription levels of both melanoma antigens were recorded by quantitative real-time polymerase chain reaction. A quantity of less than 1,000 cells per sample (average 682 cells) was sufficient for the analysis. Laser scanning cytometry estimates correlated with those of immunohistochemistry and quantitative real-time polymerase chain reaction for MART-1 and gp100. A good correlation in HLA-A2 detection by laser scanning cytometry and immunohistochemistry was also observed. Moreover, the laser scanning cytometer could discriminate subsets of cells from the same lesion with heterogeneous melanoma antigen expression, leading to the observation that cells with a DNA index greater than 2.5 expressed significantly less gp100. Thus, laser scanning cytometry yields detailed information on protein expression in individual cells and represents a new tool for dissecting the immune response in the tumor microenvironment.

A prospective, randomized, double-blind, placebo-controlled trial evaluating the effect of nystatin on the development of oral irritation in patients receiving high-dose intravenous interleukin-2.

Interleukin-2 (IL-2) has been used to treat patients with metastatic melanoma and renal cell cancer for nearly two decades, and much progress has been made in ameliorating its adverse effects. One bothersome adverse effect, oral pain or oral irritation, is usually treated with an oral antifungal antibiotic, nystatin. The authors performed a prospective, randomized, double-blind, placebo-controlled trial involving 64 patients to evaluate the effect of prophylactic administration of nystatin or placebo on the development of oral irritation in patients receiving high-dose intravenous IL-2. No difference was found between patients randomized to receive nystatin or placebo in their rates of development of oral irritation, the severity of IL-2 adverse effects, the duration of their treatment, the rate of development of positive studies for oral yeast, or their pattern of experiencing other adverse effects. Thus, patients who receive high-dose intravenous IL-2 should not be treated prophylactically with nystatin to prevent oral irritation, and clinicians should seek evidence of the presence of oral thrush before using antifungal agents to treat oral pain in these patients.