Merkel Cell Carcinoma With Gastric Metastasis and Review of Literature.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous neoplasm, with a propensity for recurrence and metastasis. Very few cases of metastases to the gastrointestinal tract have been reported in the medical literature. OBJECTIVES: The aim of this study was to report a case of MCC metastasizing to the stomach, its clinical presentation, and its management. METHODS: A PubMed search was made using the following search terms: "Merkel cell carcinoma," "gastric," and "metastasis." RESULTS: The investigators report a case of MCC metastatic to the stomach presenting with melena, syncope, early satiety, increasing fatigue, and unintentional weight loss. The other known cases of gastrointestinal metastasis of MCC are summarized and critically reviewed. CONCLUSIONS: Although MCC spreading to the stomach is exceedingly rare, because of MCC's high recurrence rate and metastatic potential, it should be considered in patients with histories of MCC presenting with recent weight loss, early satiety, and gastrointestinal bleeding.

Primitive neuroectodermal tumor of the uterus: Excellent clinical response following a multimodal treatment approach.

We present a case report of a patient with uterine primitive neuroectodermal tumor (PNET). The patient underwent surgical management followed by pelvic radiation and intravaginal brachytherapy. Following a stable interval, the patient was found to have new onset spinal, pulmonary, and adrenal metastatic disease. She was subsequently started on high dose carboplatin and etoposide. An interval reduction of her metastatic disease was observed after three cycles. We conclude that a multimodal approach, including platinum-based adjuvant chemotherapy with etoposide, can be effective in patients who present with residual or recurrent disease after surgical and radiation therapy. However, more robust studies with longer follow-up periods will be needed to establish a consensus regarding effective treatment options.

Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis.

BACKGROUND: Sorafenib is used in patients with advanced renal-cell carcinoma (RCC) or hepatocellular cancer, and its application in other types of cancers is also undergoing extensive clinical assessment. Hypertension is one of the major side-effects of this drug, and reported incidences vary substantially between clinical trials. We did a systematic review and meta-analysis of published clinical trials to establish the incidence of hypertension associated with sorafenib. The aim of this study is to gain a better understanding of the overall risk of hypertension in patients with cancer who receive sorafenib. METHODS: Databases, including Medline (July, 1966, to July, 2007), and Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 to 2007 were searched to identify relevant studies. Eligible studies were prospective clinical trials of patients with cancer assigned single-drug sorafenib at 400 mg twice daily with data on hypertension available. Incidence and relative risk (RR) of hypertension were calculated using a random-effects or fixed-effects model, depending on the heterogeneity of the included studies. FINDINGS: Nine studies published between January, 2006, and July, 2007, which included a total of 4599 patients with RCC or other solid tumours, were selected from 223 articles screened for analysis. For patients assigned sorafenib, the overall incidence of all-grade and high-grade (ie, grade 3 or 4) hypertension were 23.4% (95% CI 16.0-32.9%) and 5.7% (2.5-12.6%), respectively. No significant difference was noted between patients with RCC or a non-RCC malignancy (all grade: RR 1.03 [95% CI 0.73-1.45], p=0.89; high-grade: RR 1.23 [0.76-1.99], p=0.40) who were assigned sorafenib. Sorafenib was associated with a significantly increased risk of all-grade hypertension in patients with cancer with an RR of 6.11 (2.44-15.32], p<0.001) compared with controls. INTERPRETATION: Patients with cancer assigned sorafenib have a significant risk of developing hypertension. Appropriate monitoring and treatment is strongly recommended to prevent cardiovascular complications.

Correction: The Chemoprevention of Ovarian Cancer: the Need and the Options.

[This corrects the article DOI: 10.1007/s40495-018-0133-6.].

The Chemoprevention of Ovarian Cancer: the Need and the Options.

PURPOSE OF REVIEW: Ovarian cancer (OvCa) is the most lethal of all gynecological cancers, with a 5-year survival around 46%, mainly due to limitations in early diagnosis and treatment. Consequently, the chemoprevention of OvCa emerges as an important option to control this dismal disease. Here, we discuss the role of risk assessment in the design of chemoprevention strategies for OvCa, describe candidate agents, and assess future directions in this field. RECENT FINDINGS: OvCa chemoprevention represents an opportunity for all women, especially those at high risk such as carriers of BRCA1 or BRCA2 mutations. The use of oral contraceptives confers substantial protection against OvCa including women at high risk, which increases with longer use. Despite strong evidence for their efficacy, safety concerns and the magnitude of the requisite interventional clinical trials seem to have precluded definitive studies of oral contraceptives for this application. Several other classes of drugs, including non-steroidal anti-inflammatory drugs, retinoids, angiopreventive agents, poly(ADP-ribose) polymerase inhibitors, and tyrosine kinase inhibitors have shown promise for OvCa chemoprevention. SUMMARY: Currently, no agent is proven by interventional trials to possess chemopreventive properties against OvCa. The key opportunities in the chemoprevention of OvCa include the development of surrogate biomarkers for OvCa, the molecular definition of OvCa risk that will help select those who may benefit the most from chemoprevention, the identification of additional agents likely driven by understanding the molecular pathogenesis of OvCa, and the development of dedicated resources and support mechanisms for OvCa. Overall, there is significant optimism for the future of OvCa chemoprevention.

Optimism, distress, health-related quality of life, and change in cancer antigen 125 among patients with ovarian cancer undergoing chemotherapy.

OBJECTIVE: This study investigated whether situational and dispositional optimism were protective against dimensions of distress and aspects of health-related quality of life (HQoL) in patients with ovarian cancer undergoing chemotherapy. This study also evaluated whether optimism predicted a decrease in cancer antigen (CA) 125 levels during treatment. METHODS: Ninety women with epithelial ovarian cancer were assessed at the start and end of chemotherapy. Optimism, distress, and HQoL were measured by self-report; CA 125 levels were gathered from patients' medical charts. RESULTS: Both measures of optimism were inversely associated with baseline anxiety, perceived stress, and depression. In addition, situational optimism was positively associated with baseline social and physical well-being, and dispositional optimism was positively associated with baseline social and functional well-being. However, neither measure of optimism predicted domains of distress or HQoL at the follow-up assessment after controlling for baseline levels. Dispositional optimism predicted CA 125 at the end of treatment after controlling for baseline levels. However, neither situational nor dispositional optimism predicted CA 125 falling to normal levels (< or =35 U/mL). CONCLUSION: Consistent with prior research, optimism was inversely associated with distress and positively associated with HQoL in patients with ovarian cancer undergoing chemotherapy. Higher levels of dispositional optimism at the start of chemotherapy were associated with a greater decline in patients' CA 125 during treatment.

Toxicity, immunogenicity, and induction of E75-specific tumor-lytic CTLs by HER-2 peptide E75 (369-377) combined with granulocyte macrophage colony-stimulating factor in HLA-A2+ patients with metastatic breast and ovarian cancer.

To determine the toxicity and immunogenicity of the HER-2/neu, HLA-A2-restricted peptide E75 in patients with metastatic breast and ovarian cancer, 14 patients were vaccinated with escalating amounts of E75 (100, 500, and 1000 microg) mixed with 250 microg granulocyte macrophage colony-stimulating factor as adjuvant. Each vaccine dose was administered in a total volume of 1.5 ml divided into four intradermal injections and administered weekly for 4 weeks, followed by monthly boosts for a total of 10 injections. Vaccinations were well tolerated without significant toxicity. Blood was drawn before, at 8 weeks, and up to 13-16 months after vaccination for measurement of cellular immunity. Seven of 8 patients tested had significant delayed type hypersensitivity to E75 defined as >5 mm induration. Peripheral blood mononuclear cells from 5 of 9 patients tested proliferated to E75 with a stimulation index of > or = 2.0. Of 8 vaccinated patients tested for induction of a CTL response, 4 responded to stimulation by autologous dendritic cells plus cytokines by eliciting E75-specific lytic activity consistent with the presence of activated/memory cells, 2 others after in vitro stimulation with E75 + interleukin-12 +/- anti-CD152(33KD), whereas 2 others did not respond. Four patients with E75-specific CTLs present specifically recognized E75 on indicator tumors as demonstrated by cold-target inhibition of tumor lysis. These 4 patients showed E75-specific IFN-gamma production. peripheral blood mononuclear cell from 3 of these patients proliferated to E75, but stimulation indices were higher in the prevaccine samples. All 4 of the patients showed DTH responses to E75. These results demonstrate that vaccination with E75+ granulocyte macrophage colony-stimulating factor can induce both peptide-specific IFN-gamma and epitope specific CTLs, which lyse HER-2/neu+ tumors in stage IV patients.

Establishment and characterization of cancer cell cultures and xenografts derived from primary or metastatic Mullerian cancers.

PURPOSE: The purpose of this study was to characterize cell cultures and xenografts derived from patients with ovarian cancer. EXPERIMENTAL DESIGN: Ninety specimens from 67 patients were plated in RPMI 1640 or inoculated in nude mice. Growth characteristics of cell cultures and xenografts were determined. Expression of receptors for estrogen, progesterone, androgen, epithelial growth factor, fibroblast growth factor, HER-2/erbB-2/c-neu proto-oncogene, and the P53 expression were characterized by immunocytochemistry in 28 cell cultures. RESULTS: Forty-nine percent of samples were cultured successfully in vitro. Ascitic and pleural effusion specimens were more likely to produce a cell culture or a xenograft than solid tissue specimens (P < 0.005). All of the cell cultures had an epithelial morphology, and 89% were aneuploid with a mean DNA index of 1.6 (range, 0.9-3.0). Of 54 and 61 specimens inoculated into nude mice i.p. and s.c., 15 (28%) and 18 (30%) produced a xenograft, respectively, with two-thirds of these xenografts being reproducibly tumorigenic. The median time to first passage was 21 weeks for cell cultures and 8-12 weeks for xenografts. Expression of epithelial growth factor receptor, HER-2/erbB-2/c-neu proto-oncogene, fibroblast growth factor receptor, estrogen, progesterone, and androgen was seen in 24, 21, 31, 17, 43, and 18%, respectively. P53 was overexpressed in 62% of cell cultures analyzed. CONCLUSIONS: Ovarian cancer cells collected from effusions are easier to grow in vitro than in vivo. The only characteristic that may be associated with tumorigenicity was abnormal P53 expression. This panel of ovarian cancer materials provides useful models for biological or therapeutical studies.

Phase I study of intraperitoneal recombinant human interleukin 12 in patients with Müllerian carcinoma, gastrointestinal primary malignancies, and mesothelioma.

PURPOSE: The purpose is to determine dose-limiting toxicity, pharmacokinetics,pharmacodynamics, and immunobiology after i.p. injections of recombinant human IL-12 (rhIL-12). EXPERIMENTAL DESIGN: rhIL-12 was administered to 29 previously treated patients with peritoneal carcinomatosis from Müllerian carcinomas, gastrointestinal tract carcinomas and peritoneal mesothelioma in a Phase I trial. rhIL-12 doses were increased from 3 to 600 ng/kg. Three or more patients at each level received weekly i.p. injections of rhIL-12. RESULTS: Dose-limiting toxicity (elevated transaminase) occurred in 2 of 4 patients at the 600 ng/kg dose. More frequent toxicities included fever, fatigue, abdominal pain, nausea, and catheter-related infections. Ten patients received 300 ng/kg with acceptable frequency and severity of side effects. Two patients (one with ovarian cancer and one with mesothelioma) had no remaining disease at laparoscopy. Eight patients had stable disease and 19 progressive disease. At 300 ng/kg i.p., IL-12 was cleared from peritoneal fluid in a biphasic manner with a terminal-phase half-life of 18.7 h; peritoneal fluid levels of IL-12 5 min after i.p. injection were 100-200 pg/ml, and serum levels reached approximately 10 pg/ml between 24 and 36 h. IL-1-alpha, IL-2, IL-10, tumor necrosis factor alpha, and IFN-gamma were determined in serum and peritoneal fluid. IFN-gamma, IL-10, and tumor necrosis factor alpha were detected most frequently. Immunobiological effects included peritoneal tumor cell apoptosis, decreased tumor cell expression of basic fibroblast growth factor and vascular endothelial growth factor, elevated IFN-gamma and IFN-inducible protein 10 transcripts in peritoneal exudate cells, and increased proportions of peritoneal CD3(+) relative to CD14(+) cells. CONCLUSIONS: rhIL-12 at 300 ng/kg by weekly i.p. injection is biologically active and adequately tolerated for Phase II studies.

A phase II study of intravenous exatecan mesylate (DX-8951f) administered daily for 5 days every 3 weeks to patients with advanced ovarian, tubal or peritoneal cancer resistant to platinum, taxane and topotecan.

BACKGROUND: DX-8951f is a water-soluble camptothecin derivative with greater in vivo and in vitro activity than topotecan or irinotecan. The objectives of this phase II study were to determine the antitumor activity, safety and pharmacokinetic profile of DX-8951f administered intravenously for five consecutive days, every 3 weeks in patients with advanced ovarian, tubal and peritoneal cancer resistant to platinum, taxane and topotecan. METHODS: Enrolled in the study at The University of Texas M. D. Anderson Cancer Center were 16 patients with measurable cancer resistant to platinum, taxane and topotecan. All 16 patients were assessable for safety and 15 for efficacy analyses. Treatment consisted of a daily infusion of DX-8951f at 0.3 mg/m(2) per day (except for one minimally pretreated patient who started at 0.5 mg/m(2) per day) over 30 min for five consecutive days every 3 weeks. The pharmacokinetic and excretory profiles of DX-8951, the anhydrous form of DX-8951f, were also characterized. RESULTS: Disease was stable in 7 of 16 patients (44%) (4 minor response and 3 stable disease). The median time to tumor progression was 43 days (95% CI 37-92 days). The median overall survival was 117 days (95% CI 90-279 days). The main toxic effect was neutropenia and leukopenia with 50% of patients experiencing grade 3 or 4 neutropenia and leukopenia. One episode of neutropenic fever was observed. Grade 3 or more anemia and thrombocytopenia were seen in 25% and 13% of patients, respectively. Grade 3 nonhematologic side effects included nausea (25% of patients) and fatigue (19%). Other side effects were not more than grade 2, and included gastrointestinal dysfunction, stomatitis, dermatitis, alopecia, liver dysfunction and drug fever. DX-8951 displayed linear pharmacokinetic characteristics at the doses administered. The average plasma clearance, total volume of distribution, and terminal elimination half-life were 2.1 l/h per m(2), 20 l/m(2) and 9.5 h, respectively. CONCLUSIONS: DX-8951f administered parenterally as a single agent daily at a dose of either 0.5 or 0.3 mg/m(2) per day for 5 days is feasible in patients with advanced ovarian, tubal and peritoneal cancer resistant to platinum, taxane and topotecan. Although no responses were observed, a significant number of patients had stable disease with a decrease in CA-125 levels. In this heavily pretreated population, DX-8951f has clinically relevant hematologic and gastrointestinal toxicities in about 25% of patients. DX-8951 appeared to have linear pharmacokinetic characteristics on the basis of multiple administrations.

Treatment with HER-2 phosphorylation agonists enhance tumor ability to stimulate epitope specific CTL in vitro.

The transmembrane (TM) receptor encoded by the HER-2 proto-oncogene (HER-2) is amplified in several types of human carcinomas and premalignant states and provides an important target for cancer therapy. While overexpression of HER-2 should lead to increased CTL epitope formation due to the attendant increase in higher protein turnover, breast tumors are poor stimulators of CTL. In this report, we show that treatment of SKBR3.A2 tumor cells with HER-2 receptor agonists (EGF and NDF) enhanced tumor ability to activate CTL from tumor associated lymphocytes (TAL) and from T cells from peripheral blood in vitro. The enhanced ability of tumor cells to stimulate CTL was paralleled by tyrosine phosphorylation of HER-2, and its oligo-ubiquitination compared with control untreated, or TPA-treated tumor cells. Our results demonstrate that HER-2 ligands used at concentrations which induce tyrosine phosphorylation but not downregulation of the receptor can be used to enhance the ability of tumor cells to activate CTL. This may have implications for overcoming Ag ignorance and tolerance in human cancers.

A phase I and pharmacokinetic study of paclitaxel poliglumex and cisplatin in patients with advanced solid tumors.

PURPOSE: Determine the toxicity, maximum tolerated dose (MTD), and pharmacokinetics of paclitaxel poliglumex (PPX; CT-2103) in combination with cisplatin administered every 3 weeks. PATIENTS AND METHODS: Forty-three patients with advanced solid tumors were treated at escalating doses of PPX with a fixed dose of cisplatin at 75 mg/m(2). Conjugated and unconjugated paclitaxel were measured in plasma and urine. Cisplatin, as total platinum content in urine, was also assayed. RESULTS: Dose-limiting toxicities included neutropenia and neuropathy with a cycle 1 MTD of 210 mg/m(2). Conjugated taxanes had a prolonged half-life of >100 h. Nine patients had partial responses, and 19 had stable disease. CONCLUSIONS: PPX is a water-soluble paclitaxel-polymer conjugate with a prolonged half-life and a limited volume of distribution. PPX/cisplatin showed good activity in a refractory patient population; however, cumulative neuropathy was a significant issue at high doses, suggesting that a lower dose may be appropriate for prolonged therapy.

The associations between knowledge, CA125 preoccupation, and distress in women with epithelial ovarian cancer.

OBJECTIVE: The goal of the current study was to determine how much women with ovarian cancer know about their cancer and CA125 testing and how much women focus on or are preoccupied with their CA125 levels. We also examined the direct and moderating effects of knowledge and CA125 preoccupation on two measures of distress (depressive symptoms and anxiety). METHODS: Participants were 126 women with epithelial ovarian cancer. Patients completed questionnaires of knowledge, CA125 preoccupation, and distress at the beginning of the first or a new round of chemotherapy. RESULTS: Both knowledge and preoccupation with CA125 levels were associated with depressive and anxiety symptoms. More importantly, knowledge appeared to moderate the association between CA125 preoccupation and depressive symptoms. That is, for patients with lower levels of knowledge, more CA125 preoccupation was associated with more depressive symptoms. However, there was no such association in women with higher levels of knowledge. CONCLUSION: Our results suggest that it may be possible to decrease depressive symptoms in women who are overly preoccupied or worried about their CA125 levels by improving their knowledge of aspects of their disease and the surveillance process.

An in vitro study of inhibitory activity of gossypol, a cottonseed extract, in human carcinoma cell lines.

Gossypol, a cottonseed extract, has been shown to have antiproliferative activity in a variety of cancer cell lines. The objective of this study was to determine the inhibitory effects of gossypol on cell proliferation. Five human carcinoma cell lines were evaluated including endometrial (RL95-2), ovarian (SKOV-3), medullary thyroid (TT), and adrenocortical (NCI-H295R and SW-13). Gossypol and the metabolite, apogossypol hexaacetate, were examined at concentrations up to 500 microg ml(-1) and the IC(50) was determined using the MTT assay. Gossypol and apogossypol hexaacetate produced a dose-dependent growth inhibition in all cellular lines examined. The IC(50) for gossypol ranged from 1.3 to 18.9 microM while the IC(50) for apogossypol hexaacetate ranged from 5.2 to 9.0 microM. The results indicate that gossypol possesses antiproliferative action toward human carcinoma cells in vitro. These investigations suggest that gossypol may have therapeutic potential for the treatment of cancer.

Intraperitoneal fluid neopterin, nitrate, and tryptophan after regional administration of interleukin-12.

Activated monocytes-macrophages may be associated with antitumor activity, and activation of these cells by certain cytokines, primarily interferon gamma (IFN-gamma), can be indicated by alterations in the concentrations of neopterin, nitrate, or tryptophan. Specimens of peritoneal fluid were obtained from patients with intra-abdominal neoplasia who were undergoing treatment in a phase I trial of weekly intraperitoneal recombinant interleukin-12 (rhIL-12), an inducer of IFN-gamma. Concentrations of neopterin, nitrate, tryptophan, IFN-gamma, and tumor necrosis factor alpha (TNF-alpha) were determined at various times during the first 48 hours in 11 patients who received intraperitoneal rhIL-12 in doses ranging from 100 to 1,500 ng/kg. An increase in peritoneal fluid nitrate concentrations was observed in nine of these patients. Increased concentrations of TNF-alpha and IFN-gamma were detected in 3 of 9 and 8 of 11 patients, respectively. Increased peritoneal fluid neopterin concentrations were detected by 24 hours after the injection in all patients studied. A significant increase in the ascitic fluid neopterin level could still be detected after 1 or 2 weeks of treatment (mean +/- standard error, 7.8 +/- 1.5 nM vs. 4.6 +/- 0.3 nM; Wilcoxon test, p = 0.0019), which is consistent with monocyte-macrophage activation. In contrast, the tryptophan concentration was lower (4.7 +/- 1.1 microM vs. 6.1 +/- 1.2 microM; p = 0.0428) after 1 or 2 weeks of treatment. There was a significant correlation between the dose of rhIL-12 and posttreatment neopterin concentrations (r(s) = 0.559, p = 0.0102). The intraperitoneal delivery of rhIL-12 appears to be associated with an immediate, sustained, and dose-dependent increase in peritoneal fluid neopterin, associated in most patients by an increase in IFN-gamma and in certain patients by an increase in nitrate and a decrease in tryptophan concentrations.

Proteomic identification of heat shock protein 70 as a candidate target for enhancing apoptosis induced by farnesyl transferase inhibitor.

Farnesyl transferase inhibitors (FTIs) are novel antitumor drugs with clinical activity. FTIs inhibit cell growth not only by preventing direct Ras farnesylation but also through a Ras-independent pathway. Proteomics has been shown to be a powerful tool to monitor and analyze molecular networks and fluxes within the living cells and to identify the proteins that participate in these networks upon perturbation of the cellular environment. To observe early and dynamic protein changes in the cellular response to FTI in ovarian cancer cells, total proteins were extracted from 2774 cells treated or not with 10 microM manumycin, an FTI, for 3, 6 and 16 h. The proteins in the cells that were differentially expressed following treatment with manumycin for 3, 6 and 16 h were noted by two-dimensional electrophoresis and further identified by peptide mass fingerprinting as stress proteins. Both heat shock protein 70 (HSP70) and altered HSP70 were significantly up-regulated as early as 16 h in 2774 cells after exposure to manumycin. Since HSP70 plays an important role in protecting cells under stress, we treated the 2774 cells with the HSP inhibitor quercetin in combination with FTI. Quercetin dramatically enhanced the manumycin-mediated apoptosis in 2774 cells. Inducible HSP70 by manumycin in surviving ovarian cancer cells was also inhibited by quercetin as demonstrated by enzyme-linked immunosorbent assay. The inhibition of HSP70 by quercetin was correlated with enhancement of manumycin-induced mediated apoptosis in 2774 cells. The inhibition of HSP70 by 50 microM quercetin was also correlated with a decreased expression of procaspase-3 and enhancement of specific cleavage of poly (ADP-ribose) polymerase into apoptotic fragment in 2774 cells treated with manumycin. The interaction between the HSP70 inhibitor and FTI confirms the functional significance of the up-regulation of HSP70 as a protective mechanism against FTI-induced apoptosis and provides the framework for combination treatment of ovarian cancer.

Physiological and psychological effects of delivering medical news using a simulated physician-patient scenario.

We examined the acute stress response associated with having to deliver either bad or good medical news using a simulated physician-patient scenario. Twenty-five healthy medical students were randomly assigned to a bad medical news (BN), a good medical news (GN), or a control group that read magazines during the session. Self-report measures were obtained before and after the task. Blood pressure and heart rate were measured throughout the task period. Four blood samples were obtained across the task period. The BN and GN tasks produced significant increases in self-reported distress and cardiovascular responses compared with the control group. There was also a significant increase in natural killer cell function 10 min into the task in the BN group compared with the control group. The BN task was also somewhat more stressful than the GN task, as shown by the self-report and cardiovascular data. These findings suggest that a simulated physician-patient scenario produces an acute stress response in the "physician," with the delivery of bad medical news more stressful than the delivery of good medical news.

Phase II study of cetrorelix, a luteinizing hormone-releasing hormone antagonist in patients with platinum-resistant ovarian cancer.

OBJECTIVE: The goal of this work was to study the anticancer activity of cetrorelix, a decapeptide with LHRH receptor antagonist properties in patients with platinum-resistant ovarian cancer. About 80% of primary ovarian cancers and cell lines bear LHRH receptors. Cetrorelix has anticancer activity in in vitro and in vivo ovarian cancer models. METHODS: Eligible patients with ovarian or mullerian carcinoma resistant to platinum chemotherapy received cetrorelix 10 mg subcutaneously every day. Eligibility criteria included age > or = 18, PS < or = 2, measurable disease, chemistries and blood counts in normal range, no estrogen replacement for at least 2 weeks, and no known allergic reactions to extrinsic peptide. In patients volunteering for a biopsy, tissue was taken to perform a LHRH receptor assay. RESULTS: Seventeen patients were treated. Median age was 58 years. Median performance status was 0. Median number of prior chemotherapies was 3. Three patients had partial remissions lasting 9, 16, and 17 weeks. Toxicities effects included grade 4 anaphylactoid reaction (one patient) controlled by cortisol and cimetidine, grade 2 histamine reaction (two patients), grade 2 arthralgia (one patient) 20% cholesterol increase (two patients, who did not require specific treatment), minor hot flushes, headache, and local skin reaction at the injection site. Six of seven samples were LHRH receptor positive for mRNA and/or ligand assay. Two responding patients were LHRH receptor positive. The patient who had no receptor did not respond. CONCLUSION: Cetrorelix has activity against ovarian cancer in this refractory population, and has minimal toxicity, except for potential anaphylactoid reactions. Activity may be mediated through the LHRH receptor.

Induction of tumor-reactive CTL by C-side chain variants of the CTL epitope HER-2/neu protooncogene (369-377) selected by molecular modeling of the peptide: HLA-A2 complex.

To design side chain variants for modulation of immunogenicity, we modeled the complex of the HLA-A2 molecule with an immunodominant peptide, E75, from the HER-2/neu protooncogene protein recognized by CTL. We identified the side chain orientation of E75. We modified E75 at the central Ser(5) (E75 wild-type), which points upward, by removing successively the HO (variant S5A) and the CH2-OH (variant S5G). Replacement of the OH with an aminopropyl (CH2)3-NH3 (variant S5K) maintained a similar upward orientation of the side chain. S5A and S5G were stronger stimulators while S5K was a weaker stimulator than E75 for induction of lytic function, indicating that the OH group and its extension hindered TCR activation. S5K-CTL survived longer than did CTL induced by E75 and the variants S5A and S5G, which became apoptotic after restimulation with the inducer. S5K-CTL also recognized E75 endogenously presented by the tumor by IFN-gamma production and specific cytolysis. S5K-CTL expanded at stimulation with E75 or with E75 plus agonistic anti-Fas mAb. Compared with S5K-CTL that had been restimulated with the inducer S5K, S5K-CTL stimulated with wild-type E75 expressed higher levels of E75(+) TCR and BCL-2. Activation of human tumor-reactive CTL by weaker agonists than the nominal Ag, followed by expansion with the nominal Ag, is a novel approach to antitumor CTL development. Fine tuning of activation of tumor-reactive CTL by weak agonists, designed by molecular modeling, may circumvent cell death or tolerization induced by tumor Ag, and thus, may provide a novel approach to the rational design of human cancer vaccines.