Phase I clinical study of anti-apoptosis protein survivin-derived peptide vaccination for patients with advanced or recurrent urothelial cancer

Survivin, a member of the inhibitor of apoptosis protein family, is expressed in many malignant tumors including urothelial cancer but is hardly detectable in normal, differentiated adult tissues. Previously we reported CD8-positive cytotoxic T-lymphocytes (CTLs) were successfully induced by stimulation with survivin-2B80-88 peptide in vitro. We started a phase I clinical study of survivin-2B80-88 peptide vaccination for advanced urothelial cancer patients to assess the safety and efficacy of this vaccination. Nine patients were received vaccination and were evaluated for immunological evaluation, adverse events, and clinical responses. A total of 46 vaccinations were carried out. There was no severe adverse event. HLA-A24/survivin-2B80-88 peptide tetramer analysis revealed a significant increase in the peptide-specific CTL frequency after the vaccination in five patients. Slight reduction of the tumor volume was observed in one patient. Survivin-2B80-88 peptide-based vaccination is safe and should be further considered for potential immune and clinical efficacy in urothelial cancer patients.     

Initial experience with single-agent docetaxel as neoadjuvant therapy in men with locally advanced prostate cancer

Patients with locally advanced prostate cancer have worse outcomes after radical prostatectomy (RP) than patients with more favorable parameters. The findings of large, contemporary, RP series have led investigators at a number of centers to evaluate the potential role of neoadjuvant chemotherapy in patients with locally advanced disease. A currently ongoing study of 28 patients explores the antitumor response of a regimen of single-agent, docetaxel, 40 mg/m(2), administered intravenously on a weekly schedule for 6 weeks to patients with locally advanced prostate cancer before RP. Docetaxel has demonstrated significant antitumor activity in patients with advanced, androgen-independent disease. Study results showed that 75% of patients had reductions in prostate-specific antigen (PSA) levels ranging from 9%-79% at the completion of docetaxel therapy. In 25% of the patients, PSA levels increased by 2%-18% from baseline to completion of chemotherapy. In addition, noncastrate levels of testosterone were maintained in all patients. The docetaxel therapy has also been relatively well tolerated. Reporting of the primary endpoint of pathologic response is pending completion of accrual and surgery.     

Phase I study of a MUC1 vaccine composed of different doses of MUC1 peptide with SB-AS2 adjuvant in resected and locally advanced pancreatic cancer

MUC1 is a glycoprotein overexpressed in tumors as a hypoglycosylated form. A vaccine composed of a 100–amino acid peptide corresponding to five 20–amino acid long repeats, and SB-AS2 adjuvant, was tested in a phase I study for safety, toxicity, and ability to elicit or boost MUC1-specific immune responses. Patients with resected or locally advanced pancreatic cancer without prior chemotherapy or radiotherapy were eligible. Escalating doses of the peptide (100, 300, 1,000, and 3,000 g) were admixed with SB-AS2 and administered intramuscularly every 3 weeks for three doses, in cohorts of four patients. Sixteen patients were enrolled. Common adverse effects were grade 1 flu-like symptoms, tenderness, and erythema at the injection site. Delayed-type hypersensitivity (DTH) sites showed few or no T cells prevaccination (Pre V), but increased T-cell infiltration postvaccination (Post V). There was an increase in the percentage of CD8⁺ T cells in the peripheral blood Post V. An increase in total MUC1-specific antibody was seen in some patients, and several patients developed IgG antibody. Two of 15 resected pancreatic cancer patients are alive and disease free at follow-up of 32 and 61 months. MUC1 100mer peptide with SB-AS2 adjuvant is a safe vaccine that induces low but detectable mucin-specific humoral and T-cell responses in some patients. No difference was seen between different peptide doses. Further evaluation is warranted to examine the effect on disease-free survival and overall survival, especially in early disease and in the absence of immunosuppressive standard therapy.Work presented in part at the 36th Annual American Society of Clinical Oncology Meeting, New Orleans, LA, May 2000     

Hormonal therapy combined with radiotherapy in locally advanced prostate cancer

At present radiation therapy and radical prostatectomy are considered to be the treatment of choice for clinical T1-T2 prostate cancer. In a more advanced stage of the disease (T3) 10-year overall survival is observed in approximately 40% of patients treated with conventional radiotherapy. So far only a few methods for improving the efficacy of radiotherapy have been introduced. One of them is a three-dimensional conformal radiotherapy with 3 dimensional treatment planning. These novel methods make it possible to escalate the dose to the target and protect healthy tissue at the same time. The optimal volume of irradiation, total dose, fraction dose, techniques of radiotherapy, and the end points used during the follow-up are open to debate. In recent years a few clinical trials involving hormonal therapy and radiotherapy have been carried out. The most important of these are: RTOG 8307, RTOG 8610, RTOG 9202, and EORTC 22863.In the RTOG 8307 trial the comparison of outcomes of a combined treatment with a matched-control group of patients treated by radiotherapy alone has shown that adding hormonal therapy to radiotherapy resulted in a better outcome. Another trials RTOG 8531 and RTOG 8610 produced benefit due to the implementation of hormonal therapy in radiotherapy. The EORTC trial No. 22863 showed improvement in the 5-year overall survival when hormonal therapy after the completion of radiotherapy was continued for 3 years in the investigational arm. The RTOG 9202 study indicated benefit obtained from 2 years of adjuvant hormonal therapy.The results of these trials have had a substantial impact on the management of locally advanced prostate cancer, but there are still questions that have to be answered. There is no doubt that hormonal therapy is an important component of the management of locally advanced prostate cancer. Still the optimal combination of drugs and the timing of such treatment remains controversial. Considering the potential side effects of a combined treatment on the quality of life of patients and care costs, additional properly designed randomised trials are needed to identify the subgroup of patients who will obtain the greatest benefit. Currently, it can be concluded that in the group of patients with a high risk of relapse by adding hormonal therapy to radiotherapy the outcome of treatment in patients with prostate cancer has improved.     

A genome-wide association study of prostate cancer in West African men

Age-adjusted mortality rates for prostate cancer are higher for African-American men compared with those of European ancestry. Recent data suggest that West African men also have elevated risk for prostate cancer relative to European men. Genetic susceptibility to prostate cancer could account for part of this difference. We conducted a genome-wide association study (GWAS) of prostate cancer in West African men in the Ghana Prostate Study. Association testing was performed using multivariable logistic regression adjusted for age and genetic ancestry for 474 prostate cancer cases and 458 population-based controls on the Illumina HumanOmni-5 Quad BeadChip. The most promising association was at 10p14 within an intron of a long non-coding RNA (lncRNA RP11-543F8.2) 360 kb centromeric of GATA3 (p = 1.29E?7). In sub-analyses, SNPs at 5q31.3 were associated with high Gleason score (≥7) cancers, the strongest of which was a missense SNP in PCDHA1 (rs34575154, p = 3.66E?8), and SNPs at Xq28 (rs985081, p = 8.66E?9) and 6q21 (rs2185710, p = 5.95E?8) were associated with low Gleason score (<7) cancers. We sought to validate our findings in silico in the African Ancestry Prostate Cancer GWAS Consortium, but only one SNP, at 10p14, replicated at p < 0.05. Of the 90 prostate cancer loci reported from studies of men of European, Asian or African-American ancestry, we were able to test 81 in the Ghana Prostate Study, and 10 of these replicated at p < 0.05. Further genetic studies of prostate cancer in West African men are needed to confirm our promising susceptibility loci.     

Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer

CTLA-4 blockade has demonstrated antitumor efficacy in human clinical trials. The antitumor mechanism is presumably mediated in part by the expansion of tumor-specific T cells. Androgen deprivation, the cornerstone of treatment for patients with metastatic prostate cancer, has been shown to elicit prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with androgen deprivation, followed by an anti-CTLA-4 antibody, could augment a tumor-specific immune response elicited by androgen deprivation. We report here the results of a phase I trial evaluating a humanized monoclonal antibody targeting CTLA-4, CP-675,206 (tremelimumab), in combination with androgen deprivation using an antiandrogen. Eligible patients were those with PSA-recurrent prostate cancer after primary surgery and/or radiation therapy, not previously treated with androgen deprivation, and without radiographic evidence of metastatic disease. Subjects were treated in two cycles, 3 months apart, in which they received bicalutamide 150 mg daily days 1-28 and tremelimumab on day 29. The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose. Eleven patients were enrolled and completed at least 1 year of follow-up. Dose-limiting toxicities included grade 3 diarrhea and skin rash. No favorable changes in PSA doubling time were observed in a period shortly after completing treatment; however, three patients experienced a prolongation in PSA doubling time detectable several months after completing treatment. The identification of delayed, prolonged favorable changes in serum PSA suggests that future studies could explore this combination in studies evaluating time to disease progression.     

Results from a prostate cancer admixture mapping study in African-American men

There are considerable racial disparities in prostate cancer risk, with a 60% higher incidence rate among African-American (AA) men compared with European-American (EA) men, and a 2.4-fold higher mortality rate in AA men than in EA men. Recently, studies have implicated several African-ancestry associated prostate cancer susceptibility loci on chromosome 8q24. In the current study, we performed admixture mapping in AA men from two independent case–control studies of prostate cancer to confirm the 8q24 ancestry association and also identify other genomic regions that may harbor prostate cancer susceptibility genes. A total of 482 cases and 261 controls were genotyped for 1,509 ancestry informative markers across the genome. The mean estimated individual admixture proportions were 20% European and 80% African. The most significant observed increase in European ancestry occurred at rs2141360 on chromosome 7q31 in both the case-only (P = 0.0000035) and case–control analyses. The most significant observed increase in African ancestry across the genome occurred at a locus on chromosome 5q35 identified by SNPs rs7729084 (case-only analysis P = 0.002), and rs12474977 (case–control analysis P = 0.004), which are separated by 646 kb and were adjacent to one another on the panel. On chromosome 8, rs4367565 was associated with the greatest excess African ancestry in both the case-only and case–control analyses (case-only and case–control P = 0.02), confirming previously reported African-ancestry associations with chromosome 8q24. In conclusion, we confirmed ancestry associations on 8q24, and identified additional ancestry-associated regions potentially harboring prostate cancer susceptibility loci.     

Hospitalization for osteoarthritis and prostate cancer specific mortality among Swedish men with prostate cancer

Purpose: To examine the potential role of nonsteroidal anti-inflammatory drugs (NSAIDs) use on prostate cancer (PCa) specific mortality. Methods: We studied the association between hospitalization for osteoarthritis prior to PCa diagnosis, as a surrogate for heavy use of NSAIDs, and PCa specific mortality in a large population of PCa patients in Sweden in 1980–2004. Results: Hospitalization for osteoarthritis before PCa diagnosis was associated to a lower PCa specific mortality (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.88–0.96), but not to the risk of death from other causes (HR, 1.03; 95% CI, 0.99–1.08). The association was stronger among younger patients and patients diagnosed in earlier calendar years. Conclusions: Our data demonstrate a modestly decreased PCa specific mortality among PCa patients with hospitalization for osteoarthritis prior to PCa diagnosis, compared to those without such experience. This finding lends support to the hypothesis that NSAIDs use may influence PCa progression.     

68Ga-PSMA-HBED-CC PET/MRI is superior to multiparametric magnetic resonance imaging in men with biochemical recurrent prostate cancer: A prospective single-institutional study

BackgroundThe primary objective was to compare the overall diagnostic performance, presented as detection rate of ⁶⁸Ga-PSMA-HBED-CC positron emission tomography/magnetic resonance imaging (PSMA PET/MRI) versus conventional, multiparametric MRI (mpMRI) in a population of patients with biochemically recurrent prostate cancer. In conjunction with this analysis, secondary objectives included the evaluation of the detection rate stratified by PSA levels and primary treatment modality.MethodsA total of 165 PSMA PET MRI were performed from April 2018 to May 2021, of whom 108 were presenting for biochemical recurrent disease. The PSMA PET vertex to thigh were read by two different board-certified nuclear medicine physicians while the MRI head and neck, chest, abdomen, and pelvis (with dedicated, PI-RADS compliant multiparametric prostate MRI) were read by two board certified diagnostic radiologists.AnalysisPSMA PET/MRI had a higher detection rate than mpMRI when evaluating patients with biochemical recurrence (BCR) with similar results demonstrated when sub-analysis was performed using PSA levels, primary treatment modality, and time since androgen deprivation therapy. Our study also showed PSMA PET/MRI had a higher sensitivity than mpMRI.DiscussionOur findings demonstrate that PSMA PET/MRI is a better imaging modality in the detection of disease in the setting of BCR when compared to MRI alone. Combined utility with PSMA PET/MRI is a powerful tool which can aid in not only the detection of disease, but also guide in treatment planning for prostate cancer patients.     

Neoadjuvant chemotherapy in woman with early or locally advanced cervical cancer

Cervical cancer is a major global health problem for women. Despite the screening and vaccines available today, it continues to be the fourth most common cancer in women worldwide with 85% of cases occurring in developing countries. Standard treatments for early or locally advanced cervical cancer are surgery (S) or concomitant chemo-radiotherapy (CT-RT). Neoadjuvant chemotherapy (NACT) prior to surgery or radiotherapy has been proposed and tested in clinical trials and has been included in clinical practice in some countries.In order to determine the true role of NACT either prior to S or RT in terms of achieving benefits in OS or DFS, randomized clinical trials and meta-analyses published from its beginnings to the present have been searched and analyzed in this study.The analysis of published clinical trials shows that NACT followed by S and NACT followed by RT have failed to demonstrate benefits in OS or DFS. Clinical trials comparing NACT followed by S versus exclusive RT have also been analyzed, where NACT followed by S could not show benefits for RT either.ConclusionAdding neoadjuvant chemotherapy to S or RT cannot be recommended outside the context of clinical trials.     

Adiponectin as a potential marker of prostate cancer progression: studies in organ-confined and locally advanced prostate cancer

Serum levels of adiponectin were measured in patients with benign prostatic hyperplasia and prostate cancer of pT2 and pT3 stage. Adiponectin ELISA assay, immunohistochemistry, and selected metabolic and biochemical parameters measurement was performed in 25 patients with benign prostatic hyperplasia and 43 with prostate cancer (17 patients with organ-confined and 26 patients with locally advanced disease). Serum adiponectin levels did not differ between prostate benign hyperplasia and cancer clinical stage T2, but was significantly higher in pT3 relative to pT2 group (14.51+/-4.92 vs. 21.41+/-8.12, P = 0.003). Tissue immunohistochemistry showed enhanced staining in neoplastic prostate glands and intraepithelial neoplasia relative to benign prostatic hyperplasia without distinction between disease grade and stage. Serum adiponectin levels are higher in locally advanced relative to organ-confined prostate cancer and may thus serve as an auxiliary marker providing further improvement for discrimination between pT2 and pT3 stages.