Biomedical subjects

A E Chang

Publications and source records attributed to A E Chang.

At least 109 records · Page 6Linked to original sources

PubMed1989

Determinants of survival in patients with unresectable colorectal liver metastases.

Prognostic indicators in 67 patients with unresectable colorectal liver metastases were analyzed. These patients were identified to have isolated hepatic metastases after extensive radiological evaluation and demonstrated good performance status without evidence of liver failure. Univariate analysis revealed 6 of 22 factors that were associated with survival: alkaline phosphatase (AP), lactic dehydrogenase (LDH), occult intra-abdominal extrahepatic disease, percent hepatic replacement by tumor (PHR), sex, and carcinoembryonic antigen (CEA). A multivariate analysis identified two independent factors that jointly influenced survival: AP and PHR. Patients with an AP greater than 175 U/liter had a greater than threefold relative risk of dying compared with patients with AP less than or equal to 175 U/liter (P = 0.0001). Patients with PHR II or III (25-75%, greater than 75%) also had a greater than threefold relative risk of dying compared with patients with PHR 1 (less than 25%; P = 0.0074). Our patient population is typical of that being entered into trials examining experimental therapies. Alkaline phosphatase and extent of liver involvement by tumor are significant prognostic indicators that should be accounted for in such studies.

Aged↗

PubMed1989

Extremity soft tissue sarcomas: analysis of prognostic variables in 300 cases and evaluation of tumor necrosis as a factor in stratifying higher-grade sarcomas.

From July 1975 to February 1985, 300 patients with extremity soft tissue sarcomas (STS) were entered into treatment protocols at the National Cancer Institute. Using the Cox proportional hazards model, the STS were analyzed for independent prognostic variables that had significant association with disease-free and overall survival. The effects of adjuvant treatment were also included in the analysis. Percent tumor necrosis was the basis for separating intermediate and high-grade STS (less than 15% necrosis = grade 2; greater than 15% necrosis = grade 3). The most important prognostic variable was histologic grade, which was highly associated with relative risk of metastasis and fatal outcome (P less than .0001). Histologic type of STS was not a significant prognostic variable in predicting metastases. Patients with tumors located on the proximal or middle part of the extremity had a fivefold increased risk of death (P = .02) compared with patients who had STS located more distally. Mitotic activity (P = .0005) and vascular invasion (P = .0034) were also associated with malignant behavior, but histologic grade was the most significant predictor of outcome. Histologic grade of malignancy was based upon a combination of tumor typing and visual estimation of extent of tumor necrosis; using these two features, one can reliably separate low-grade (i.e., grade 1) from high-grade STS and also stratify the more aggressive (i.e., grade 2 and 3) tumors. Over the 9.5-year period of study, the tumor-related mortality was as follows: grade 1 (1/38), 3%; grade 2 (19/142), 13%; and grade 3 (45/120), 38%.

Adult↗

PubMed1989

Overview of interleukin-2 as an immunotherapeutic agent.

Interleukin-2 (IL-2) is a lymphokine which has a variety of in vivo immunomodulatory effects. The administration of IL-2 can mediate enhancement of cellular immune responses, induction of lymphocyte proliferation, production of cytokines, and regression of established tumor in animal models. The availability of large quantities of recombinant IL-2 has enabled investigators to examine its therapeutic potential in the treatment of human cancer. Several studies have documented the ability of IL-2 administration to cause durable tumor regression in patients with advanced melanoma and renal cell cancer. Toxicity of therapy is dose related and is mediated by a vascular capillary leak syndrome, lymphocytic infiltration, and the release of cytokines secreted in response to IL-2 administration. The side effects are completely reversible upon cessation of therapy. Future efforts are aimed at increasing the antitumor efficacy and decreasing the toxicity of IL-2 administration.

Animals↗

PubMed1989

Distinct immunologic specificity of tumor regression mediated by effector cells isolated from immunized and tumor-bearing mice.

Sensitized T lymphocytes can mediate potent antitumor effects when transferred to tumor-bearing animals. Employing the MCA 105 and MCA 106 sarcomas, we were able to generate antitumor effector cells by immunization of syngeneic mice with tumor cells admixed with Corynebacterium parvum. These immune splenocytes could be further sensitized and expanded in culture by the in vitro sensitization (IVS) method utilizing tumor stimulator cells and IL-2. Adoptive immunotherapy of pulmonary metastases mediated by noncultured splenocytes from immunized mice or immune IVS cells showed exquisite specificity between the two sarcomas. These results demonstrate the presence of tumor-specific antigens on MCA 105 and MCA 106 tumor cells which can serve as target molecules for immunotherapy. Recently, we have generated therapeutic T lymphocytes from mice bearing progressively growing tumors by the IVS method. However, IVS cells from tumor-bearing mice showed cross-reactivity between the MCA 105 and 106 sarcomas in adoptive immunotherapy experiments. Since these IVS cells did not affect other control tumors, the limited cross-reactivity suggests the presence of common tumor-associated antigens on MCA 105 and MCA 106 tumor cells which can also serve as the target for tumor rejection. Therefore, immune responses to progressive tumor growth and to immunization are distinct with respect to antigen recognition by T lymphocytes.

Animals↗

PubMed1989

Iododeoxyuridine (IdUrd) incorporation into DNA of human hematopoietic cells, normal liver and hepatic metastases in man: as a radiosensitizer and as a marker for cell kinetic studies.

Iododeoxyuridine (IdUrd) was administered as a continuous infusion for 14 days to patients with glioblastoma and sarcoma, and for 3 days to patients with metastatic colorectal carcinoma. In the first group, the maximum incorporation of IdUrd into DNA was determined, taking granulocytes as parameter. In the second group, selective incorporation into DNA of normal liver and hepatic metastases of colorectal cancer was investigated. The highest dose of 675 mg/sq.m./day for 14 days produced IdUrd plasma concentrations of 1.8 +/- 0.3 microM, and a substitution of dThd by IdUrd in the range of 7.1-11.7%. Coadministration of fluorodeoxyuridine did not show significant enhancement of IdUrd-incorporation in granulocytes. Three-day intravenous infusions of IdUrd 1000 mg/sq.m./day produced 1.7-4.5% IdUrd-incorporation in hepatic metastases. Three-day intraarterial infusions (hepatic artery) produced 3.8-10.5% dThd-replacement, whereas, in 9/10 patients this was less than 1% in normal liver. In tumor tissue there was a trend towards FdUrd-modulated enhancement of IdUrd-incorporation, although there was considerable scatter. Cell kinetic studies revealed that IdUrd-incorporation in monocytes and granulocytes was very similar. In lymphocytes, a much lower fraction incorporated IdUrd. Liver tumor contained a considerably higher fraction of IdUrd-labeled cells, compared with normal liver. Potential doubling times for the tumors were estimated to be 10 days.

Cell Cycle↗

PubMed1989

Liver metastases: detection with MR imaging at 0.5 and 1.5 T.

Nineteen patients with known liver metastases were examined with two magnetic resonance (MR) pulse sequences at 0.5 T and three pulse sequences at 1.5 T. In addition, the patients were studied with computed tomography (CT) enhanced with ethiodized oil emulsion-13 (EOE-13). At 0.5 T a spin-echo (SE) 300/22 (repetition time/echo time, msec) sequence prospectively demonstrated 92.4% of the detectable liver metastases, while an SE 2,000/80 sequence showed 52.1% of the lesions. At 1.5 T, an SE 300/25 sequence depicted 68.3% and an SE 2,000/80 sequence 71.6%, while the more T1-weighted inversion recovery (IR) 2,000/600 (repetition time/inversion time, msec) sequence demonstrated 89.5% of the lesions. EOE-13 CT scans depicted 93.3%. These findings suggest that T1-weighted imaging is as successful at demonstrating liver metastases at 1.5 T with an IR 2,000/600 sequence as at 0.5 T with an SE 300/22 sequence. At both field strengths, MR imaging of the liver is comparable to state-of-the-art CT.

Humans↗

PubMed1989

A phase I study of intraarterial iododeoxyuridine in patients with colorectal liver metastases.

Regional delivery of iododeoxyuridine (IdUrd) to patients with colorectal liver metastases was examined in a phase I study. The maximum-tolerated intraarterial (IA) dose (MTD) was 1,333 mg/m2/d administered continuously for 14 days. The dose-limiting toxicity was thrombocytopenia. Thrombocytopenia and leukopenia were correlated with the amount of IdUrd incorporated into DNA of peripheral granulocytes. In contrast to our experience with 5-fluorodeoxyuridine, there was no evidence of hepatobiliary toxicity. In 11 patients who received IA IdUrd alone, seven had a greater than or equal to 50% decrease in carcinoembryonic antigen (CEA) levels, with five having tumor volume reductions of 65%, 48%, 46%, 44%, and 27%. Thus, IA IdUrd alone has antitumor efficacy. Patients subsequently received IdUrd in combination with external beam radiation to a total dose of 2,400 cGy without acute local toxicity. In addition to these favorable clinical findings, we have previously shown that IdUrd is selectively incorporated into tumor DNA compared with normal liver in these patients. Further phase II evaluations of this approach are warranted.

Antineoplastic Agents↗

PubMed1989

Functional and psychosocial effects of multimodality limb-sparing therapy in patients with soft tissue sarcomas.

We have documented functional and psychosocial changes in patients with extremity soft tissue sarcomas who have undergone multimodality limb-sparing treatments. In 88 patients, parameters related to economic status, sexual activity, pain, limb function, and global quality of life (QOL) were recorded prior to surgery and every 6 months postoperatively. Changes from the preoperative assessment for every parameter were analyzed in each patient. Six months after surgery, there was a decrease in employment status, sexual activity, and in limb function in a significant number of patients. At 12 months, these decreases were still evident. Despite these changes, global QOL measured by a standardized test showed at least some improvement in a significant proportion of patients at 12 months. These findings highlight the difficulty in defining QOL. It could not be ascertained if radiation therapy and/or chemotherapy were causative factors in specific changes because of the small numbers of patients in each subgroup. However, among 60 patients with high-grade sarcomas, significant wound problems developed in 10 of 33 who received postoperative radiation therapy in combination with adjuvant doxorubicin and cyclophosphamide chemotherapy compared with one of 27 patients who received adjuvant chemotherapy alone (P = .016). Also, among high-grade sarcoma patients with 12-month follow-up, six of 19 patients who received radiation therapy and chemotherapy developed joint contractures compared with zero of 15 patients who received chemotherapy alone (P less than .04). The combination of postoperative radiation therapy and chemotherapy appeared to be associated with significantly more tissue-related injury in patients with high-grade sarcomas compared with chemotherapy alone.

Adolescent↗

PubMed1989

Prospective evaluation of hepatic imaging studies in the detection of colorectal metastases: correlation with surgical findings.

Nineteen patients with isolated colorectal liver metastases were preoperatively evaluated with five hepatic imaging studies. The results of these studies were correlated with operative findings. One study involved the use of EOE-13, an intravenously administered lipid contrast agent that enhances liver parenchyma on computed tomography (CT) scans (EOE-CT). Another study, arterial portography (AP-CT), was performed with injection of a water-soluble contrast agent into the superior mesenteric artery during CT scanning. Delayed CT scanning (DS-CT) was completed 4 hours after AP-CT. In addition, T1- and T2-weighted magnetic resonance imaging (MRI) (T1-MRI, T2-MRI) scans were done. All patients subsequently underwent laparotomy with identification of 78 lesions. A lesion-by-lesion analysis revealed that the sensitivity of EOE-CT (83%), AP-CT (78%), DS-CT (82%), and T1-MRI (84%) was comparable. T2-MRI had a significantly lower sensitivity (64%) compared with EOE-CT, DS-CT, and T1-MRI. The false-positive rate for AP-CT was 31%, which was significantly higher than that of all other studies. The T1-MRI examination had the lowest false-positive rate and proved to be the best hepatic imaging study in the detection of colorectal metastases. EOE-CT and DS-CT were comparable, whereas AP-CT and T2-MRI proved to be inferior tests.

Colorectal Neoplasms↗

PubMed1989

Differences in biodistribution of indium-111-and iodine-131-labeled B72.3 monoclonal antibodies in patients with colorectal cancer.

We have compared the biodistributions of [131I]B72.3 and 111In-SCN-Bz-DTPA B72.3 monoclonal antibody (MoAb) in patients with metastatic colon cancers. B72.3 is an IgG1 that recognizes a mucin-like colon cancer associated antigen. Eight patients were infused with 3-5 mCi and 0.36-20 mg of 111In-labeled B72.3 prepared with a bifunctional chelate, isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA). The biodistribution was compared with that of 13 patients previously studied as part of a separate trial, with 1-10 mCi and 0.16-1.35 mg of [131I]B72.3. The Beta T1/2 in serum was 63 +/- 5 hr for 111In-SCN-Bz-DTPA B72.3 and 52 +/- 10 hr for [131I]B72.3. Whole-body retention of the 111In (T1/2 = 11.8 days) was significantly longer than for [131I]B72.3 (T1/2 = 3.3 days), p less than 0.000001. The 131I was excreted primarily through the urine. Urinary excretion of 111In was low and gamma camera images confirmed that some 111In was excreted in the bowel. Tumor localization was seen in one of seven evaluable patients receiving 111In-SCN-Bz-DTPA B72.3. Gamma camera images showed that the liver concentrates 111In but not 131I. We conclude that 111In-SCN-Bz-DTPA B72.3 is metabolized in a different manner from the iodinated B72.3. The high concentration and prolonged retention of 111In by the liver interferes with tumor imaging of metastases.

Antibodies, Monoclonal↗

PubMed1989

Development of antitumor reactivity in regional draining lymph nodes from tumor-immunized and tumor-bearing murine hosts.

With use of the weakly immunogenic MCA 105 tumor of the C57BL/6 mouse, the antitumor reactivity of lymphoid cells derived from the regional draining lymph nodes (RLN) of tumor-immunized and tumor-bearing mice was examined. Mice were immunized with an inoculation of viable tumor admixed with Corynebacterium parvum. Excision of tumor immunization sites within 4 days abrogated the development of systemic immunity to reject a tumor challenge. However, excision of the immunization site on day 6 did not interfere with the development of systemic antitumor immunity. In subsequent experiments, tumor immunization sites were excised on day 6 in all mice and the RLN either left intact or excised on day 6 or day 14. The development of systemic tumor immunity was severely impaired if RLN were excised on day 6, indicating the pivotal role of the RLN. Excision of the RLN on day 14 had no impact on the development of systemic immunity, thus indicating that the requirement for the RLN was time dependent. In mice bearing progressively growing tumors, lymphoid cells derived from RLN were examined for therapeutic efficacy in adoptive immunotherapy experiments. Although fresh RLN cells harvested 6 and 14 days after tumor inoculation did not demonstrate inherent therapeutic efficacy, after in vitro sensitization with irradiated tumor cells and interleukin-2, these RLN cells acquired significant antitumor activity in adoptive immunotherapy experiments. These data indicate that RLN are essential in the development of tumor immunity and may be used as a source of therapeutic effector cells for adoptive immunotherapy.

Animals↗

PubMed1988

Adoptive immunotherapy of microscopic and advanced visceral metastases with in vitro sensitized lymphoid cells from mice bearing progressive tumors.

Lymphocytes from mice bearing the weakly immunogenic MCA 105 sarcoma contained pre-effector cells that could be sensitized and expanded in vitro to acquire anti-tumor reactivity. The in vitro sensitization (IVS) required antigenic stimulation by tumor cells and the presence of IL-2 for cellular proliferation. Recent work has also demonstrated that IVS cells could be generated in an IL-2 concentration as low as 2 U/ml. In the present study, we have evaluated therapeutic efficacy of IVS cells generated in different concentrations of IL-2 against advanced metastases established in the lung as well as in the liver. Treatment of microscopic or grossly visible pulmonary metastases established for 3 or 10 days by systemic transfer of IVS cells resulted in significant reductions of the numbers of metastases. On a per cell basis, IVS cells generated in 2 U/ml of IL-2 exhibited at least twofold greater reactivity than cells generated in 1000 U/ml of IL-2. In survival experiments, treatment of established microscopic (day 3) and visible (day 10) pulmonary metastases with 1.5 x 10(7) and 3 x 10(7) IVS cells generated in 2 U/ml of IL-2 resulted in prolongation of survival and cure of the disease in 60 and 30% of animals, respectively. The systemic anti-tumor effect of IVS cells was further investigated in mice with hepatic metastases. Treatment of day 3 microscopic hepatic metastases revealed that as little as 1.2 X 10(7) IVS cells generated in 2 U/ml of IL-2 reduced the mean number of metastases from more than 250 in various control groups to 32. Evaluation by survival demonstrated that transfer of 1.7 x 10(7) and 3.8 x 10(7) IVS cells was capable of prolonging the survival and curing 40 and 30% of mice bearing day 3 and day 9 hepatic metastases, respectively. Again, IVS cells generated in 2 U/ml of IL-2 were more effective therapeutically than cells generated in 1000 U/ml of IL-2. In all experiments, mice were also given IL-2 to enhance the in vivo reactivity of IVS cells. However, the doses of IL-2 alone had no therapeutic benefit. Taken together, our results show that adoptive immunotherapy with IVS cells generated from tumor-bearing mice was an effective means of eliminating advanced metastases in various visceral organs.

Animals↗

PubMed1988

Cellular basis of immunologic interactions in adoptive T cell therapy of established metastases from a syngeneic murine sarcoma.

The adoptive transfer of specifically sensitized T lymphocytes can effectively mediate the regression of established local and metastatic tumors. Previous experiments using the weakly immunogenic MCA 105 sarcoma indicated that cellular interactions between transferred L3T4+ helper and Lyt-2+ cytotoxic immune T cells were necessary for mediating tumor regression. In this study, the kinetics of T-T cell interactions were analyzed by in vivo depletion of T cell subsets with mAb. The anti-tumor efficacy of transferred immune cells was abrogated by in vivo administration of either L3T4 or Lyt-2 mAb on the day of cellular therapy. However, if mAb were given 3 days after the transfer of immune cells, depletion of Lyt-2+ but not L3T4+ cells abrogated anti-tumor efficacy. T cell depletion on day 6 after transfer of immune cells had no adverse effect on tumor regression, indicating the period required for T cell reactivity in vivo. Furthermore, depletion of Ia+ cells by in vivo mAb treatment abrogated the anti-tumor efficacy of immune cells. It is thus hypothesized that there are two distinct but sequential phases of in vivo T cell interactions leading to the regression of established tumors after adoptive immunotherapy. An initial "helper/inducer" phase apparently requires the interaction of L3T4+ immune cells and the tumor Ag involving Ia+ cells. The inducement of L3T4+ cell activation is to provide helper function via the secretion of IL-2. The second phase designated as an "effector phase" involves differentiation of immune Lyt-2+ cells under the influence of IL-2 secreted during the helper/inducer phase for generation of mature Lyt-2+ effector cells. To further support the hypothesis of a two-phase process we have examined the phenotype and kinetics of tumor regression mediated by effector cells generated by secondary in vitro sensitization (IVS). Although the IVS cells were generated from fresh MCA 105 immune spleen cells, their anti-tumor efficacy was mediated solely by Lyt-2+ lymphocytes. Kinetic studies revealed that the in vivo requirement of IVS Lyt-2+ effector cells to mediate tumor regression was less than 3 days, and the anti-tumor reactivity of these cells was not affected by in vivo depletion of Ia+ cells. Thus, the IVS reaction is likely representative of the in vivo counterpart of the helper/inducer phase leading to the generation of mature Lyt-2+ immune effector cells. Tumor regression after transfer of Lyt-2+ cells generated in IVS therefore required a relatively shorter period of time than that required after the transfer of fresh noncultured MCA 105 immune spleen cells.

Animals↗

PubMed1988

Generation of therapeutic T lymphocytes from tumor-bearing mice by in vitro sensitization. Culture requirements and characterization of immunologic specificity.

We have previously established an in vitro sensitization (IVS) procedure with which lymphocytes from tumor-bearing mice could be expanded and sensitized to acquire antitumor reactivity capable of mediating the regression of established pulmonary metastases from the weakly immunogenic MCA 105 murine sarcoma. Culture conditions required for the optimal generation of therapeutic effector cells were evaluated in the current study. Generation of effector cells by IVS required stimulation by intact tumor cells. Tumor cells killed by heat or disrupted by sonication were ineffective, but the antigenicity of tumor cells was not affected by gamma-irradiation. Long term established tumor cell lines could also serve as antigenic stimulator cells albeit with lower efficiency than fresh tumor cells. IL-2 was essential for cellular proliferation during IVS. The concentration of 1000 U/ml of IL-2 also induced nonspecific lymphokine-activated killer (LAK) activity. However, cytotoxic cells were generated during IVS in response to a broad range of IL-2 concentrations. At low IL-2 concentrations (2 to 10 U/ml), IVS cells were generated which displayed little or no LAK activity, had a greater therapeutic efficacy than those generated with high concentrations of IL-2 (100 to 1000 U/ml). Despite having high LAK activity, IVS cells, from cultures where IL-2 was added 3 or more days after initiation, had no therapeutic effect. Thus, the generation of therapeutic cells occurred independently of LAK cell production. Adoptive immunotherapy with IVS cells from MCA 105 tumor-bearing mice demonstrated cross-reactivity with the immunologically distinct MCA 106 but not the nonimmunogenic MCA 102 tumor. In contrast, IVS cells from MCA 106 tumor-bearing mice exhibited specific in vivo reactivity. In vitro cytotoxicity analyses revealed that IVS cells from MCA 105 and MCA 106 tumor-bearing mice were able to lyse both MCA 105 and MCA 106 target cells, but the reactivity toward inoculating tumors was highest. Considering previous findings that the MCA 105 and MCA 106 sarcomas possessed distinct tumor-specific transplantation Ag, the cross-reactivity observed in this study suggests that the immune response during progressive tumor growth may be different from that elicited in response to active immunization.

Animals↗

PubMed1988

Intra-abdominal extrahepatic disease in patients with colorectal hepatic metastases.

The resection of hepatic metastases in patients with extrahepatic disease is of no proven benefit. Preoperative identification of extrahepatic disease may prevent unnecessary laparotomy. Preoperative evaluation including physical examination, computed tomography of the abdomen, full lung tomography or chest-computed tomography, and radionuclide bone scanning identified extrahepatic metastases, most commonly in the lung, in 25 of 132 patients with purported isolated liver metastases. Of 107 patients with negative staging evaluations, intra-abdominal extrahepatic metastases were found in 26 percent (28 of 107) at laparotomy, most commonly in portal and celiac lymph nodes. The presence of extrahepatic disease correlated with greater than 25 percent hepatic replacement by tumor, presence of symptoms, and Dukes' C primary lesions; however, none was predictive. We were unable to develop a model to preoperatively predict the presence of intra-abdominal extrahepatic disease. The authors recommend a preoperative evaluation including physical examination, and computed tomographic scans of the abdomen and chest. A bone scan is required only in patients with symptoms referable to bone. Despite a negative preoperative evaluation, however, a considerable proportion of patients with colorectal hepatic metastases will have extrahepatic disease at the time of abdominal exploration.

Abdominal Neoplasms↗

PubMed1988

Selective incorporation of iododeoxyuridine into DNA of hepatic metastases versus normal human liver.

Fourteen patients received 5-iodo-2(1)-deoxyuridine (IdUrd) before surgery for placement of a hepatic arterial catheter. Biopsy specimens were obtained at the time of surgery and incorporation of IdUrd into deoxyribonucleic acid (DNA) in tumor and normal hepatic tissue was measured by HPLC and used as an index of drug selectivity. Over a 3-day intravenous infusion of IdUrd at 1000 mg/m2/day, substitution for thymidine in tumor DNA averaged 3.1%. Normal hepatic DNA contained less than 1% substitution by IdUrd. Arterial delivery of IdUrd increased levels in DNA, whereas modulation with fluorodeoxyuridine produced mixed results. In six patients, flow cytometric analysis showed that the tumor contained a median of 32% of tumor cells that had incorporated IdUrd in 3 days, corresponding to a potential doubling time of only 10 days. Thymidylate synthetase activity in tumors was 20-fold greater than in normal liver tissue, whereas thymidine kinase activity was twofold greater in tumors. These pharmacologic studies encourage further clinical trials of IdUrd as a cytotoxic agent or radiosensitizer.

Adult↗

PubMed1988

Perioperative blood transfusions are associated with decreased time to recurrence and decreased survival after resection of colorectal liver metastases.

Data from fifty-five patients who had hepatic resections for colorectal liver metastases at the National Cancer Institute (NCI) were analyzed to determine the effect of perioperative blood transfusions on disease recurrence and overall survival. Besides blood transfusions, other factors included in the analysis were size, number, and distribution of metastases, margin status of resected metastases, length of disease-free interval, Duke's stage of the primary tumor, type of hepatic resection, and anesthesia time. Using the Cox proportional hazards model, the amount of blood transfused was found to be a significant prognostic factor. For each additional unit of blood transfused the risk of disease recurrence and death was increased by 5% (p = 0.0015) and 7% (p = 0.0013), respectively. The median disease-free survival for patients who received 3-5, 6-10, and greater than or equal to 11 transfused units was 26, 12.1, and 11.4 months, respectively. The median overall survival for patients who received 3-5, 6-10, and greater than or equal to 11 transfused units was greater than 44, 39.2, and 33.6 months, respectively. The number of resected nodules (1-2 vs. greater than or equal to 3), type of resection (anatomic lobectomy vs. wedge resection), and nodule size (less than or equal to 3.0 cm vs. greater than 3.0 cm) were additional factors that were further evaluated to determine the effect of blood transfusions. Analyses stratified for each of these factors revealed that patients who received greater than or equal to 11 units of blood had a significantly decreased disease-free and overall survival compared with patients who received 3-10 units of blood. It is concluded that the amount of perioperative blood transfused is an independent prognostic factor that adversely effects disease-free and overall survival.

Adult↗

PubMed1988

Immunotherapy of patients with advanced cancer using tumor-infiltrating lymphocytes and recombinant interleukin-2: a pilot study.

Clinical investigations using the adoptive transfer of lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) to treat patients with advanced cancer have yielded encouraging results. We have thus sought ways to enhance the effectiveness of adoptive immunotherapy while minimizing its toxic side effects. Murine experiments have identified tumor-infiltrating lymphocytes (TIL) as killer cells more effective than LAK cells and less dependent on adjunctive systemically administered IL-2 to mediate antitumor effects. Accordingly, we performed a pilot protocol to investigate the feasibility and practicality of administering IL-2-expanded TIL to humans with metastatic cancers. Twelve patients, including six with melanoma, four with renal cell carcinoma, one with breast carcinoma, and one with colon carcinoma, were treated with varying doses and combinations of TIL (8.0 X 10(9) to 2.3 X 10(11) cells per patient), IL-2 (10,000 to 100,000 U/kg three times daily to dose-limiting toxicity), and cyclophosphamide (CPM) (up to 50 mg/kg). Two partial responses (PR) to therapy were observed: pulmonary and mediastinal masses regressed in a patient with melanoma, and a lymph node mass regressed in a patient with renal cell carcinoma. One additional patient with breast cancer experienced a partial regression of disease in lymph nodal and cutaneous sites with complete elimination of malignant cells from a pleural effusion, although cutaneous disease recurred at 4 weeks. The toxicities of therapy were similar to those ascribed to IL-2; no toxic effects were directly attributable to TIL infusions. In five of six melanoma patients, TIL demonstrated lytic activity specific for the autologous tumor target in short-term chromium-release assays, distinct from the nonspecific lytic activity characteristic of LAK cells. This study represents an initial attempt to identify and use lymphocyte subsets with enhanced tumoricidal capacity in the adoptive immunotherapy of human malignancies.

Adult↗