Harrington Cancer Center

Abstract Background: brainstem metastases (BSM) is a rare site of occurrence and their management is a challenging issue. Based on the lack of evidences, the optimal radiation treatment of BSM remains controversial. We evaluated the efficacy and toxicity of linear accelerator (linac)-based stereotactic radiosurgery (SRS) and steretotactic radiotherapy (SRT) in the treatment of BMS in a series of patients treated in different centers. Methods: we conducted a multicentric retrospective study of patients affected by 1-2 BSM from different solid who underwent SRS/SRT. Freedom from local progression (FLP), cancer-specific survival (CSS), overall survival (OS), and toxicity were evaluated. Moreover, predictive factors of treatment response and survival were evaluated.Results: Between 2008 and 2021, 105 patients with 111 BMS received SRS or SRT for 1-2 BSM. Median follow-up time was 10 months (range 3-130). One-year FLP rate was 90.4%. At the univariate analysis, tumor volume ≤0.4 cc and concomitant target therapy were associated with longer FLP, with concomitant target therapy that remained a significant independent predictor [0.058, HR 0.139 (95% CI 0.0182-1.064]. Median OS and CSS were 11 months and 14.6 months, respectively. At multivariate analysis, concomitant target therapy administration was significantly associated with longer OS [HR 0.514 (95%CI 0.302-0.875); p=0.01]. Neurological death occurred in 30.4% of patients, although this was due to BSM progression in only 3 (2.8%) patients. Conclusion: brainstem metastases can be safely treated with linac-based SRS with apparent no detrimental effect on survival. When treated with ablative intent, BSM are an uncommon cause of neurological death. Future prospective trial should answer the question of whether BSM should be excluded a priori from clinical trial.

PIX306 was a phase 3, randomised, single-blind, multicentre trial conducted in adult patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) grade 3 who relapsed after ≥1 rituximab-containing regimen and were not eligible for a stem cell transplant. Patients were randomised 1:1 to pixantrone 50mg/m2 or gemcitabine 1000mg/m2 on days 1, 8 and 15 of a 28-day cycle, combined with rituximab 375mg/m2 on day 1, for up to six cycles. Patients were followed for up to 96weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), complete response (CR) rate, overall response rate (ORR) and safety. Overall, 312 patients were randomised (median age 73·0years). The study did not meet its primary endpoint. Median PFS [95% confidence interval (CI)] was 7·3months (5·2-8·4) with pixantrone+rituximab (PIX+R) and 6·3months (4·4-8·1) with gemcitabine+rituximab [GEM+R; hazard ratio (HR): 0·85; 95% CI 0·64-1·14; P=0·28]. Median OS was 13·3 (10·1-19·8) months with PIX+R and 19·6 (12·4-31·9) months with GEM+R (HR: 1·13; 95% CI 0·83-1·53). ORR was 61·9% and 43·9% respectively and CR rate 35·5% and 21·7%. The incidence of adverse events, including cardiac events, was not statistically significant different between PIX+R and GEM+R.

Expression of Migration inducting gene-7 (Mig-7) is limited to tumor cells and to date not found in normal tissues. Multiple tumor microenvironment factors, such as epidermal and hepatocyte growth factors, in concert with alphavbeta5 integrin ligation, induce Mig-7 mRNA expression. Gain or loss of Mig-7 protein studies shows that Mig-7 promotes invasion of colon and endometrial carcinoma cells. These data led us to hypothesize that targeting Mig-7 through various methods could decrease invasion, enhance monocyte cell killing of tumor cells, and inhibit disease progression. To begin testing this hypothesis, an in vitro chemoinvasion assay of endometrial carcinoma cells treated with Mig-7-specific or control antibodies was used. Mig-7 antibody significantly reduced invasion by >60% compared with controls. In another approach to test this hypothesis, an in vitro analysis of peptide-stimulated human peripheral blood monocyte cells and their killing of MCF-7 breast carcinoma cells was used. Mig-7 peptide treatment increased monocyte cell tumor necrosis factor expression and killing of MCF-7 cells 30-fold over no peptide stimulation and 3-fold over MUC-1 or control peptide treatments. Furthermore, stably expressing Mig-7-specific short hairpin RNA resulted in significantly reduced Mig-7 protein levels and early primary tumor growth in a xenograft nude mouse model. Reduced phosphorylation of ERK1/2, Akt, and S6 kinase as well as decreased membrane-type 1 matrix metalloproteinase activity were mechanisms through which Mig-7 protein caused these effects. Based on these collective data, Mig-7 expression could be a potential candidate for future targeted cancer therapies.

Dosimetry measurements of a 131Cs brachytherapy source have been performed in liquid water employing thermoluminescence dosimeters. A search of the literature reveals that this is the first time a complete set of dosimetric parameters for a brachytherapy "seed" source has been measured in liquid water. This method avoids the medium correction uncertainties introduced by the use of water-equivalent plastic phantoms. To assure confidence in the results, four different sources were employed for each parameter measured, and measurements were performed multiple times. The measured dosimetric parameters presented here are based on the AAPM Task Group 43 formalism. The dose-rate constant measured in liquid water was (1.063 +/- 0.023) cGy h(-1) U(-1) and was based on the air-kerma strength standard for this source established by the National Institute of Standards and Technology. Measured values for the 2D anisotropy function and the radial dose function are presented.

The aim of this study was to determine the feasibility of two treatment regimens for ovarian cancers: (1) combined intraperitoneal/intravenous (IP/IV) cisplatin/paclitaxel; or (2) IV only carboplatin/paclitaxel; both followed by 12 cycles of maintenance paclitaxel. A total of 102 subjects were identified who underwent surgery for stage III ovarian cancer. All subjects received either IV or IV/IP chemotherapy, and had a complete response. The subjects were then prescribed maintenance paclitaxel IV for an additional 12 months. Demographic and clinical data were analyzed. Forty-five subjects received combined IP/IV chemotherapy versus 57 who received IV therapy alone. IP/IV versus IV administration was not associated with differences in age, ethnicity, tumor histology, or incidence of intestinal surgery. Toxicities included fatigue, neuropathy, myelosuppression, and nausea/vomiting in both groups. In the IP/IV group, 29/47 subjects (61.7%) completed 12 cycles of maintenance paclitaxel versus 18/55 (32.7%) in the IV group (P = 0.006). The mean number completed by the IP/IV group was 8.6, while the IV group completed 5.8 cycles (P = 0.002). In subjects who received <12 cycles, the mean number of cycles completed by the IP/IV group was 3.1 versus 2.8 in the IV group. The reasons for stopping included neuropathy (33), fatigue (8), myelosuppression (7) and disease progression (6). Patients who received combined IP/IV chemotherapy were more likely to complete maintenance therapy than those who only received IV chemotherapy. Patients who stop maintenance therapy usually do so early in the course. Additional resources directed at physical and emotional support during early cycles of maintenance chemotherapy may allow more to complete the regimen.

Neoplastic cells often aberrantly express normal testicular proteins. Because these proteins have a very restricted normal tissue expression, they may be suitable targets for immunotherapy. SLLP1 is an intra-acrosomal, nonbacteriolytic, c lysozyme-like protein recently isolated from human spermatozoa. In this study, we determined whether SLLP1 is a novel cancer-testis antigen in hematologic malignancies SLLP1 expression in hematologic tumor cells and normal tissues was determined using a combination of reverse transcription-PCR, real-time PCR, and Western blot analysis. The presence of antibodies against SLLP1 was determined by ELISA analysis. SLLP1 was aberrantly expressed in the tumor cells from 2 of 9 acute myeloid leukemia, 3 of 11 chronic lymphocytic leukemia, 4 of 14 chronic myeloid leukemia, and 6 of 17 multiple myeloma. In contrast, they were not detected in corresponding specimens from any healthy donors. SLLP1 exhibited a very restricted normal tissue expression, being found only in testis/spermatozoa. SLLP1 was expressed in some tumor cells at a level of >25%. High titer IgG antibodies against SLLP1 were also detected in the sera of some of these patients. SLLP1 is a novel cancer-testis antigen in hematologic malignancies and is capable of eliciting B-cell immune responses in vivo in cancer-bearing individuals. Our results, therefore, support SLLP1 as a protein target appropriate for additional in vitro study to define its suitability for immunotherapy.

The authors previously identified sperm protein 17 (Sp17) as being expressed in patients with multiple myeloma. The restricted expression of Sp17 in normal tissue makes it an ideal target for tumor vaccine. In the current study, the authors extended their research to include ovarian carcinoma. A pair of sequence specific primers was used in reverse transcriptase-polymerase chain reaction to determine the gene expression of Sp17. A recombinant Sp17 protein was used with monocyte-derived dendritic cells and autologous peripheral blood mononuclear cells to generate Sp17 specific cytotoxic T-lymphocytes (CTLs). The successful generation of Sp17 specific CTLs was confirmed using standard (51)chromium-release assays. Sp17 was found to be expressed in the primary tumor cells from 70% of the patients with ovarian carcinoma. Human leukocyte antigen (HLA) class I- restricted Sp17 specific CTLs were generated successfully from the peripheral blood of three patients with ovarian carcinoma at the time of disease presentation. These CTLs were able to lyse autologous Epstein-Barr virus-transformed lymphoblastoid cells in a Sp17-dependent manner. Target lysis was HLA class I-dependent and could be blocked by antibodies against monomorphic HLA class I but not HLA class II molecules. The CTLs also lysed Sp17-positive autologous tumor cells, suggesting that Sp17 is processed and presented in association with the HLA class I molecules in Sp17- positive tumor cells in a concentration and configuration that could be recognized by recombinant protein-primed CTLs. Tumor cell killing by the CTLs appeared to be mediated through the perforin pathway. Flow cytometric analysis of the CTLs indicated that they predominantly were CD8 in phenotype and produced interferon-gamma and scant amounts of interleukin-4. The results of the current study suggest the potential of Sp17 as a target for immunotherapy in patients with ovarian carcinoma.

All the steroidal anti-inflammatory drugs currently available are glucocorticoids. The desired anti-inflammatory activities of glucocorticoids frequently are accompanied by adverse side effects, notably glycogenic activities and profound immunosuppression, that can limit clinical use. We recently identified 16-epiestriol, a naturally occurring steroid, as exhibiting significant anti-inflammatory activity without glycogenic activity. In the present study, we compared the effects of 16-epiestriol and hydrocortisone on the capacity of murine splenocytes to produce interferon-y (IFN-y). We injected young adult male BDF1 mice once with 20 mg/kg hydrocortisone or 20, 5, or 1 mg/kg 16-epiestriol and 4 h later harvested the splenocytes. Flow cytometric analysis confirmed that 16-epiestriol did not alter the number of CD3+ T cells in the spleen. In contrast to the suppressive effects of hydrocortisone, none of the 16-epiestriol concentrations inhibited concanavalin A-stimulated IFN-gamma production by spleen cells, as determined by ELISA. Incubating spleen cells from untreated mice in concentrations of 16-epiestriol ranging from 1 mg/ml to 100 pg/ml did not alter profiles of IFN-gamma production, in contrast to the suppressive dose-response effects of hydrocortisone. Collectively, these results support the contention that 16-epiestriol may be a clinically useful safe anti-inflammatory steroid without profound immunosuppressive activities.