Dramatic response to single-agent atezolizumab in a patient with MSI-H serous ovarian cancer.

WHAT IS KNOWN AND OBJECTIVE: Patients with ovarian cancer have not benefited substantially from immunotherapy. We report a case of ovarian cancer, however, that responded well to the programmed cell death-ligand 1 inhibitor atezolizumab. CASE SUMMARY: A 64-year-old woman with recurrent ovarian carcinoma, not responsive to platinum/taxane and bevacizumab therapy, was BRCA normal but showed loss of MLH1 and PMS2 proteins. She was treated with atezolizumab. After the third cycle, her CA 125 levels decreased to normal. Radiologic evaluation showed a near-complete response. WHAT IS NEW AND CONCLUSION: Identifying response markers is important when choosing therapy for ovarian cancer patients.

Contact lens care solutions downregulate membrane-associated mucins 1 and 16 in cultured human corneal epithelial cells and at the rat corneal surface in vivo.

OBJECTIVE: The purpose of this study was first to evaluate the effect of multipurpose contact lens care solutions (MPSs) on the expression of membrane-associated mucins (MUC1 and MUC16) in SV40-transformed human corneal epithelial (HCE-T) cells and in vivo rat cornea. The second aim of this study was to determine the role of the common MPS additive boric acid in reducing mucin expression and release. METHODS: The HCE-T cells were exposed to different concentrations of MPS-F, MPS-G, MPS-H, MPS-I, and MPS-J with 100% treatment for 30 minutes and 10% treatment for 24 hours. MUC1 and MUC16 expressions were subsequently analyzed by Western blotting. Wister rats were also subjected to MPS-A, MPS-B, MPS-C, MPS-D, and MPS-E and received phosphate-buffered saline exposure (1 drop in the right eye every 10 minutes for 1 hour). The left eye was used as control. Cornea sections and lysates were used for the immunohistochemical assay of MUC1 and MUC16 expressions. Conditioned media from treated HCE-T cells were also analyzed using Western blotting. RESULTS: The MPSs containing boric acid downregulated MUC1 and MUC16 in the rat cornea, whereas MPSs without boric acid had no effect as demonstrated by the Western blotting and immunohistochemical analysis. Conditioned media from MPS-containing boric acid revealed some trace of MUC16. CONCLUSIONS: The clinical use of MPSs containing boric acid that reduce MUC1 and MUC16 availability should be avoided. Additionally, the presence of MUC16 in the conditioned media suggests that boric acid may have enhanced cleavage of MUC16 at the cell membrane surface.

Phase I study and preliminary pharmacology of the novel innate immune modulator rBBX-01 in gynecologic cancers.

PURPOSE: A recombinant protein product, rBBX-01, is the first innate immunostimulator derived from a protozoan (Eimeria protozoan) and has shown potent preclinical in vivo and in vitro activities. This phase I trial was done to determine the safety and basic pharmacology of rBBX-01. EXPERIMENTAL DESIGN: Eligible patients had recurrent incurable gynecologic malignancies. The study was divided into three components: a starting low-dose phase (0.85, 2.0, and 4.0 microg/m2), an intrapatient dose acceleration phase (4.0-1,024.0 microg/m2), and a high-dose phase (1,000 and 2,000 microg/m2). All treatment doses were administered daily for 5 days. Patients were allowed a second cycle of treatment if there was evidence of response. RESULTS: Sixteen patients received a total of 20 cycles of rBBX-01. All patients tolerated the drug well, exhibiting no local or systemic, acute or delayed, adverse reactions. Plasma levels of rBBX-01 were detectable in all patients over the entire dose range, although changes in the pharmacodynamic marker (interleukin-12) exhibited patient-to-patient variability. Of 14 patients with ovarian, primary peritoneal, or endometrial cancer with elevated CA125 biomarkers at the start of treatment, 4 responded with decreased levels of CA125. One patient showed decreasing CA125 levels for 10 months and received no additional chemotherapy for 11 months. Those patients exhibiting reductions in CA125 also exhibited increased levels of plasma interleukin-12 during the week of therapy. CONCLUSION: The immunostimulator rBBX-01 was safe in multidose regimens in heavily pretreated women. Of the 14 patients with elevated CA125 levels, an approximately 30% response rate was detected. rBBX-01 should receive additional testing in the clinical setting.

Development and in vitro validation of anti-mesothelin biobodies that prevent CA125/Mesothelin-dependent cell attachment.

Preventing peritoneal implantation of carcinoma cells could prolong ovarian cancer patient remission and survival. Peritoneal cells constitutively express mesothelin, a ligand for CA125 that is expressed by tumor cells. Thus blocking CA125/mesothelin-dependent cell attachment may prevent or delay peritoneal metastatic recurrence. We developed a high-throughput screening system for reagents able to block CA125/mesothelin-dependent cell attachment with a sensitive quantitative readout. Using a novel yeast-expression system to produce secreted, in vivo biotinylated proteins and biobodies (Bbs), we generated anti-mesothelin Bbs. Anti-mesothelin Bbs derived from high affinity yeast-display scFv detected both membrane-bound and soluble mesothelins and inhibited CA125/mesothelin-dependent cell attachment.

[Correlation between the effect of chemotherapy on complement conformation and on CA-125 antigen in the blood plasma of patients with ovarian carcinoma].

Correlation was investigated between blood-plasma levels of C3(H2)O (conformation pattern of C3 component of the complement) and tumor-associated marker CA-125 in patients with ovarian cancer before and after chemotherapy. Since a drop in CA-125 level after chemotherapy was associated with similar changes in C3(H2)O fraction, it seems reasonable to suggest that change in conformation of C3 is a response of the immune system to cancer.

Successful treatment of ovarian cancer with apatinib combined with chemotherapy: A case report.

RATIONALE: The standard treatment for ovarian cancer is chemotherapy with 2 drugs (taxanes and platinum drugs). However, the traditional combination of the 2 drugs has many adverse effects (AEs) and the cancer cells will quickly become resistant to the drugs. Apatinib is a small-molecule antiangiogenic agent which has shown promising therapeutic effects against diverse tumor types, but it still remains unknown whether apatinib has an antitumor effect in patients with ovarian cancer. Herein, we present a successfully treated case of ovarian cancer using chemotherapy and apatinib, in order to demonstrate the effectiveness of this new combined regimen in ovarian cancer. PATIENTS CONCERNS: A 51-year-old Chinese woman presented with ovarian cancer >4.5 years. The disease and the cancer antigen 125 (CA-125) had been controlled well by surgical treatment and following chemotherapy. However, the drugs could not control the disease anymore as the CA-125 level was significantly increasing. DIAGNOSIS: Ovarian cancer. INTERVENTIONS: The patient was treated with apatinib combined with epirubicin. Apatinib was administered orally, at an initial daily dose of 500 mg, and was then reduced to 250 mg qd after the appearance of intolerable hand-foot syndrome (HFS) and oral ulcer. Then, the oral ulcer disappeared and the HFS was controlled by dose adjustment, oral vitamin B6, and hand cream application. OUTCOMES: The CA-125 reverted to the normal value after treatment with the new regimen. Magnetic resonance imaging showed that the original tumor lesions had disappeared. Apatinib monotherapy as maintenance therapy was then used to successfully control the cancer with a complete response. Our study is the first, to our knowledge, to report the therapeutic effects of apatinib and epirubicin on ovarian cancer. LESSONS: Apatinib combined with chemotherapy and apatinib monotherapy as maintenance therapy could be a new therapeutic strategy for ovarian cancer, especially adenocarcinomas.

A phase I-II preoperative biomarker trial of fenretinide in ascitic ovarian cancer.

PURPOSE: To evaluate study feasibility, toxicity, drug concentrations, and activity of escalating doses of the synthetic retinoid fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] in ovarian cancer by measuring serum CA125 and cytomorphometric biomarkers in cancer cells collected from ascitic fluid before and after treatment. METHODS: Twenty-two naive patients with ascitic ovarian cancer were treated with escalating doses of 4-HPR at 0, 400, 600, and 800 mg/d for 1 to 4 weeks before surgery. Changes in the proportion of proliferating cells expressed by Ki67 and computer-assisted cytomorphometric variables (nuclear area, DNA index, and chromatin texture) were determined in ascitic cells. Drug levels were measured by high-performance liquid chromatography. RESULTS: Doses up to 800 mg/d were well tolerated, and no adverse reactions occurred. There was no effect of 4-HPR on changes in serum CA125, Ki67 expression, which were assessed in 75% of subjects, and cytomorphometric variables, which were assessed in 80% of subjects. Plasma retinol levels were significantly lower in affected women than healthy donors. 4-HPR plasma concentrations increased slightly with increasing doses and attained a 1.4 micromol/L concentration with 800 mg/d. Drug levels in malignant ascitic cells and tumor tissue were higher than in plasma but were 50 and 5 times lower, respectively, than in carcinoma cells treated in vitro with 1 micromol/L 4-HPR. CONCLUSIONS: Cell biomarkers can be measured in ascitic cells to assess drug activity. Under our experimental conditions, 4-HPR did not show activity in advanced ovarian cancer cells. However, clinical evidence supports further investigation of fenretinide for ovarian cancer prevention.

Paclitaxel- and docetaxel-dependent activation of CA-125 expression in human ovarian carcinoma cells.

Taxanes represent a new class of antineoplastic agents that are being evaluated in several malignant tumors; they have been shown to induce a high remission rate and to prolong survival in ovarian cancer patients. However, CA-125 has been suggested to be an unreliable marker for monitoring response to paclitaxel therapy. Therefore, we were interested in whether taxanes may directly modulate CA-125 expression. Human ovarian carcinoma cell lines OVCAR-3, HOC-7, SKOV-6, 2780, 2774, and HTB-77 were treated with paclitaxel or docetaxel. Secreted, surface-associated, and cytosolic CA-125 were estimated by means of a sandwich solid-phase RIA or by immuno-flow cytometry. In addition to in vitro antiproliferative activity, paclitaxel and docetaxel augmented the expression of the tumor marker CA-125 in the three ovarian carcinoma cell lines, OVCAR-3, HOC-7, and SKOV-6, constitutively expressing this tumor marker. The three CA-125-negative cell lines, 2780, 2774, and HTB-77, did not respond to taxane treatment by expressing this tumor marker, although their proliferation was markedly inhibited. The taxane-mediated induction of CA-125 was found to be dependent on intact protein and RNA biosynthesis. However, CA-125 concentration was increased in the supernatant medium only and not on cell surface or cytosol. Our results demonstrate an in vitro activation of ovarian carcinoma cells in terms of CA-125 secretion by taxanes. This may explain the CA-125 fluctuations observed in vivo under paclitaxel treatment and may indicate that CA-125 is not a reliable tumor marker during taxane chemotherapy.

Biological and pharmacological characterisation of three models of human ovarian carcinoma established in nude mice: use of the CA125 tumour marker to predict antitumour activity.

In an attempt to improve the relevance of human tumour xenografts to the clinical situation, we have established 3 models of human ovarian carcinoma (IGROV1, A2780 and NIH:OVCAR-3) in nude mice in which progressive peritoneal carcinomatosis resulted in the death of tumour-bearing animals (median survival times: 32, 40 and 64 days, respectively). Histological analyses revealed both common and different characteristics in growth patterns and dissemination profiles. In each case, three stages of the disease were defined (early, intermediate and late). The antitumour activities of adriamycin, cisplatin, cyclophosphamide and paclitaxel were then compared when administered at the early stage where small multifocal tumour nodules were detectable in the peritoneal cavity of the animals. Significant antitumour activities of cisplatin and particularly paclitaxel were noted in terms of increase in survival time of the treated mice (T/C values for IGROV1, A2780 and NIH:OVCAR-3 respectively: 152%, 167%, and 187% for cisplatin and 211%, 179% and >283% for paclitaxel), paclitaxel being curative against the NIH:OVCAR-3 xenograft. These results reflect the high efficacy of these two drugs in the clinic in the treatment of ovarian carcinoma. The clinically used CA125 tumour marker, not detectable in healthy mice, was measured in the serum of mice bearing IGROV1 and NIH:OVCAR-3 tumours. CA125 serum levels increased as a function of time and were well correlated to disease progression. Moreover, treatment with cisplatin and paclitaxel led to significant decreases in these levels of between 58% and 100%. This human serum marker could be used to predict early on the efficacy of chemotherapy in these two models. In conclusion, the three experimental ovarian carcinomas possess several important characteristics of the human disease and may thus be used as a screen to select new antitumour drugs potentially active in this pathology.

Treatment of endometriosis with a decreasing dosage of a gonadotropin-releasing hormone agonist (nafarelin): a pilot study with low-dose agonist therapy ("draw-back" therapy).

OBJECTIVE: To evaluate the efficacy of half-dose GnRH agonist therapy for endometriosis. DESIGN: Prospective, longitudinal pilot study. SETTING: Osaka University Hospital. PATIENT(S): Patients with symptomatic endometriosis. INTERVENTION(S): Fifteen patients were randomized to receive either full-dose nafarelin treatment (200 microgram b.i.d.) for 24 weeks (n = 7) or full-dose nafarelin treatment for 4 weeks followed by half-dose nafarelin treatment (200 microgram daily) for 20 weeks (n = 8). MAIN OUTCOME MEASURE(S): Clinical symptoms and the results of physical examinations. Serum E(2) and carcinoma antigen 125 (CA125) levels, lipid profiles, and urinary levels of the N-telopeptide of type I collagen. Bone mineral density of the lumbar spine. RESULT(S): Subjective and objective manifestations of endometriosis were decreased to a similar extent in both study groups. Adverse effects were markedly reduced with half-dose administration. In the half-dose group, the mean serum E(2) level was significantly suppressed by 4 weeks of treatment with full-dose nafarelin and remained at approximately 30 pg/mL with half-dose nafarelin. Loss of bone mineral density was significantly less with half-dose treatment. CONCLUSION(S): Half-dose administration of nafarelin after pituitary down-regulation with full-dose nafarelin ("draw-back" therapy) is a new protocol for the treatment of endometriosis that is effective and associated with fewer adverse effects.

Comparison of the effects of leuprorelin acetate and danazol treatments on serum CA-125 levels in women with endometriosis.

OBJECTIVE: To investigate the effects of danazol and leuprorelin acetate on CA-125 levels during treatment for endometriosis. PATIENTS AND METHODS: Fifty women with laparoscopically diagnosed and treated endometriosis, and 50 women without pelvic disease as a control group. Following surgical treatment, 35 women with endometriosis were divided into two groups. The first group (20 women) received 200 mg danazol three times daily for 6 months; the second group (15 women) received 3.75 mg leuprorelin acetate depot every 28 days for 6 months. Serum CA-125 levels were measured before medical treatment, during the last 15 days of the 6-month treatment course, and 3 months after treatment. RESULTS: Serum CA-125 levels were significantly higher in women with endometriosis than in women in the control group. Before treatment, CA-125 levels in patients with stage III/IV endometriosis were significantly higher than those in stage I/II endometriosis. Six months of danazol or leuprorelin acetate depot treatment decreased serum CA-125 levels. Three months after stopping danazol, CA-125 levels remained significantly lower than pretreatment levels. On the other hand, 3 months after stopping leuprorelin acetate, CA-125 levels returned to pretreatment levels. CONCLUSIONS: (a) Danazol and leuprorelin acetate are equally effective in the treatment of endometriosis. (b) Moreover, the results support the view that the determination of CA-125 levels may assist in evaluating progress of endometriosis treatment.

Elevated serum CA-125 in tuberculous peritonitis: report of a case.

A 37-year-old female presented with a 2-month history of abdominal distention. Omentum masses with massive ascites were found and ovarian cancer with peritoneal carcinomatosis was suspected. Her serum CA-125 level was over 500 U/ml before therapy. Tuberculous peritonitis was diagnosed via peritoneal biopsy. The serum CA-125 level returned to normal after antituberculous therapy. Elevated serum CA-125 does not always indicate ovarian malignancy. This tumor marker may be used to monitor the disease activity in non-neoplastic ascitic states.

[Changes in the levels of tumor markers in those working with different chemically active substances]. / Izmenenie urovnei opukholevykh markerov u rabotaiushchikh s razlichnymi khimicheski aktivnymi veshchestvami.

Groups at risk for malignant neoplasia were identified among workmen occupationally exposed to different chemical substances, using immunoradiometric and enzyme immunoassays of tumor-associated antigens. Exposure to the above occupational hazard was found to affect the workmen and cause certain chronic illness accompanied by some increase in concentration of a number of tumoral markers. Increase in tumour antigens suggests indirectly that the chemical substances may have carcinogenic activity. We have every reason to recommend these tests as an additional method for identification of groups at high risk for subsequent development of tumours in the digestive system and reproductive organs of persons occupationally exposed to chemical substances.

A peritoneal dialysis regimen low in glucose and glucose degradation products results in increased cancer antigen 125 and peritoneal activation.

BACKGROUND: Glucose and glucose degradation products (GDPs) in peritoneal dialysis fluids (PDFs) are both thought to mediate progressive peritoneal worsening. METHODS: In a multicenter, prospective, randomized crossover study, incident continuous ambulatory peritoneal dialysis patients were treated either with conventional lactate-buffered PDF (sPD regimen) or with a regimen low in glucose and GDPs: Nutrineal×1, Extraneal×1, and Physioneal×2 (NEPP regimen; all solutions: Baxter Healthcare, Utrecht, The Netherlands). After 6 months, patients were switched to the alternative regimen for another 6 months. After 6 weeks of run-in, before the switch, and at the end of the study, 4-hour peritoneal equilibration tests were performed, and overnight effluents were analyzed for cells and biomarkers. Differences between the regimens were assessed by multivariate analysis corrected for time and regimen sequence. RESULTS: The 45 patients who completed the study were equally distributed over both groups. During NEPP treatment, D(4)/D(0) glucose was lower (p < 0.01) and D/P creatinine was higher (p = 0.04). In NEPP overnight effluent, mesothelial cells (p < 0.0001), cancer antigen 125 (p < 0.0001), hyaluronan (p < 0.0001), leukocytes (p < 0.001), interleukins 6 (p = 0.001) and 8 (p = 0.0001), and vascular endothelial growth factor (VEGF, p < 0.0001) were increased by a factor of 2-3 compared with levels in sPD effluent. The NEPP regimen was associated with higher transport parameters, but that association disappeared after the addition of VEGF to the model. The association between NEPP and higher effluent levels of VEGF could not be attributed to glucose and GDP loads. CONCLUSIONS: Study results indicate preservation of the mesothelium and increased peritoneal activation during NEPP treatment. Whether the increase in VEGF reflects an increase in mesothelial cell mass or whether it points to another, undesirable mechanism cannot be determined from the present study. Longitudinal studies are needed to finally evaluate the usefulness of the NEPP regimen for further clinical use.

Effect of low-dose oral etoposide on serum CA-125 in patients with advanced epithelial ovarian cancer.

The effect of oral etoposide on CA-125 serum levels was evaluated in 17 patients with epithelial ovarian cancer and progressive disease during, or relapsing after, prior chemotherapy. Only three patients had measurable lesions at extraperitoneal sites. Five had no measurable lesions. The oral etoposide dose was 50 mg b.d. for 7 days every 3 weeks, escalating to 10 or 14 days and continued until clinical progression. CA-125 after 4 courses was compared to baseline (CA-125 ratio). The rate of change of CA-125 (s, slope of the exponential regression curve) during the first 4 courses was compared to s over a similar period before treatment. One patient had a clinical partial response. Two other patients had a biochemical response (CA-125 ratio <0.5). Although the biochemical response rate was modest (12.5%), a decrease of s was observed in 14/16 patients (P = 0.02). The mean change of s represented an increase of mean doubling time from 52 to 693 days. No patients were withdrawn because of toxicity. General malaise, nausea, diarrhea, and anemia were the most important side effects. At the given dose schedule, oral etoposide shows activity in advanced ovarian cancer if the rate of change of CA-125 is used as a measure of activity.

Effect of topotecan on serum CA-125 in patients with advanced epithelial ovarian cancer.

The effect of topotecan on CA-125 serum levels was evaluated in 30 patients with advanced epithelial ovarian cancer. All patients had progressive disease and were relapsing during (11 patients) or after (19 patients) chemotherapy containing paclitaxel and platinum. Topotecan (1.0 mg/m(2)/day) was administered intravenously on Days 1-5 every 3 weeks. The patients had received a median of 2 (1-5) prior regimens. Four patients had increased CA-125 only, and 26 had both measurable disease and increased CA-125. Two patients (7%) achieved a clinical partial response with durations of 5 and 10+ months, respectively. Eighteen other patients (60%) exhibited no clinical change with a median duration of 5+ months (range: 2-11+ months). Among these patients 9 (30%) had a biochemical response. The rate of change in CA-125 (s, slope of the exponential regression curve) during treatment with topotecan was compared with s over a period before treatment. A decrease in s was observed in 20 patients (74%). Comparing the mean values of s before and during topotecan, a significant (P = 0.005) decrease was seen in the CA-125 serum levels. The mean doubling times before and during treatment were 59 and 1421 days, respectively. Toxicity was mainly hematologic. Neutropenia grades III and IV were seen in 16 and 10 patients, respectively. No patients died due to side effects. Generally the side effects were mild to moderate. In conclusion, at the given dose intensity topotecan shows activity in advanced paclitaxel- and platinum-resistant ovarian cancer based on CA-125 measurements.